Dr Ming Yang

Senior Lecturer

School of Biomedical Sciences and Pharmacy (Immunology and Microbiology)

Career Summary

Biography

Dr. Yang graduated from The John Curtin School of Medical Research, Institute of Advanced Studies, Australian National University, with distinction: he was awarded the prestigious Frank Fenner Medal for the  most  outstanding  PhD  dissertation.  Subsequently he was awarded  a prestigious University of Newcastle Research Fellowship and was promoted to level B within the first year after graduation.  Based on his research directions and productivity, he was awarded an NHMRC New Investigator grant. In 2012, he was promoted to Senior Research Fellow. He is now internationally known for his investigations into the pathogenesis of asthma, and the molecular and cellular regulation of inflammation.

Dr. Yang’s group has received international recognition through publication in leading biomedical science journals and has contributed to more than 30 refereed manuscripts in high impact journals (J Exp Med, J Clin Invest, Gastroenterology, J Allergy Clin Immunology, PNAS, J Immunology) with more than 1500 combined citations. He has been successful in obtaining research grants both independently and in collaboration with other investigators (over $3.8 Million). 

Research Directions and Significant Achievements:

In recent years Dr. Yang has initiated investigations into the mechanisms that regulate steroid resistant inflammatory pathways in the lung, to help understand how steroid resistance may develop in asthma. Understanding the mechanisms that regulate steroid-resistant inflammation is important and developing novel non- steroidal therapeutic approaches to the disease will be highly beneficial, as these patients suffer greater morbidity and mortality. Currently, there is no effective treatment and there is very limited functional evidence of the way in which the inflammatory pathways are activated in these patients. Building on clinical studies, we have recently demonstrated, for the first time, that macrophages are crucial in regulating steroid-resistant inflammatory signals. Two papers have been published in the Journal of Immunology and their significance has been recognised by the American Academy of Asthma Allergy and Immunology (symposium invitation, 2010) and the invitation to write two reviews for Current Drug Targets and Journal of Leukocyte Biology.

The unique complexity of respiratory system has limited the development of therapeutic agents that show clinical benefit for severe asthmatic patients. However, the more efficient therapeutics may be developed by silencing the dominant proinflammatory genes, which are responsible for the propagation of the disease. Employing small ‘non-coding’ RNA molecules called microRNAs (miRNA), small interfering RNAs (siRNA) or synthetic analogues of these molecules, ‘antagomirs’, to specifically silence aberrant gene function is of growing interest. Dr. Yang was at the forefront of the first application of RNA interference to modulate AHR and macrophage function in the lung (2006, J Immunology). His works in this field has been recognised by invitations to write reviews for Drug Discovery Today, Pharmacology & Therapeutics and American Journal of Respiratory Cellular and Molecular Biology. Recently, he has been investigating the central roles of miRNA in the regulation of the pro-inflammatory effects of macrophages and thus potential innate immune mediated AHR. Dr. Yang also has extensive research interests in characterizing the pivotal roles of these small non-coding RNAs in modulating the differentiation and function of granulocytes and other immune cells.

Research Expertise
- Immunology - Pharmacology - Pharmaceutical Sciences

Collaborations
Dr. Yang has productive collaborations within Australia and oversea internationally renowned groups. He has extensive academic, intellectual and procedural input into these collaborations and has also contributed significant experimental expertise. These collaborations will continue for the foreseeable future.

Qualifications

  • PhD, Australian National University

Keywords

  • Immunology
  • Pharmacology
  • Haematopoiesis
  • Gene Regulation
  • Infectious Disease
  • Respiratory Disease
  • Inflammation Inhibition
  • Pharmaceutical Sciences
  • Intracellular Signalling Transduction

Fields of Research

Code Description Percentage
110299 Cardiorespiratory Medicine and Haematology not elsewhere classified 80
110399 Clinical Sciences not elsewhere classified 20

Professional Experience

UON Appointment

Title Organisation / Department
Senior Lecturer University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia
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Publications

For publications that are currently unpublished or in-press, details are shown in italics.


Chapter (1 outputs)

Year Citation Altmetrics Link
2013 Yang M, Lin D, 'Genetic Variations in MicroRNA-Encoding Sequences and MicroRNA Target Sites Alter Lung Cancer Susceptibility and Survival', MicroRNAs in Medicine 343-351 (2013)

© 2014 by John Wiley & Sons, Inc. All rights reserved. Lung cancer is one of the leading causes of cancer death around the world, with more than 1,000,000 deaths each year. ... [more]

© 2014 by John Wiley & Sons, Inc. All rights reserved. Lung cancer is one of the leading causes of cancer death around the world, with more than 1,000,000 deaths each year. It is well known that more than 75% of lung cancer is attributed to environmental carcinogen exposure, such as tobacco smoking. However, not all exposed individuals develop lung cancer, suggesting that the genetic makeup is also important in the development of this malignancy. It has been found that single-nucleotide polymorphisms (SNPs) in the pre-microRNA (miRNA) genes alter miRNA processing and expression and, therefore, could contribute to lung cancer susceptibility and survival. Several SNPs in miRNA target sites of oncogenes or tumor suppressor genes can affect miRNA-messenger RNA (mRNA) interaction and have been associated with lung cancer risk, alone and in combination with tobacco smoking. In this chapter, we summarize the impact of genetic variants in miR-encoding sequences or miRNA target sites on lung cancer risk or survival.

DOI 10.1002/9781118300312.ch20

Journal article (161 outputs)

Year Citation Altmetrics Link
2018 Chen YD, Zhang N, Qiu XG, Yuan J, Yang M, 'LncRNA CDKN2BAS rs2157719 genetic variant contributes to medulloblastoma predisposition', Journal of Gene Medicine, 20 (2018)

Copyright © 2017 John Wiley & Sons, Ltd. Background: How germline single nucleotide polymorphisms are involved in the etiology of medulloblastoma remans poorly understood. W... [more]

Copyright © 2017 John Wiley & Sons, Ltd. Background: How germline single nucleotide polymorphisms are involved in the etiology of medulloblastoma remans poorly understood. We hypothesized that CCDKN2A/B rs1063192 and rs4977756 and also the long noncoding RNA (lncRNA) CDKN2BAS rs2157719 glioma susceptibility polymorphisms identified by genome-wide association studies may contribute to medulloblastoma predisposition. Methods: To test this hypothesis, we genotyped these genetic variants among 160 medulloblastoma patients and 443 health controls in a Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. Results: We found that only the lncRNA CDKN2BAS rs2157719 T>C genetic polymorphism was significantly associated with an increased medulloblastoma risk (C allele: OR = 1.85, 95% CI = 1.32¿2.58; p = 2.7 × 10¿4). The stratified analyses showed an elevated risk of pediatric medulloblastoma associated with CDKN2BAS rs2157719 CC or TC genotype (both p < 0.05). Moreover, the association between the CDKN2BAS rs2157719 polymorphism and medulloblastoma risk is more pronounced in males (OR = 2.22, 95% CI = 1.36¿3.62; p = 0.001). Conclusions: The findings of the present study provide important insights into the genetic complexities and predisposition of medulloblastoma in Chinese, especially at the lncRNA germline variation level.

DOI 10.1002/jgm.3000
Citations Scopus - 1
2018 Liu C, Yuan L, Zou Y, Yang M, Chen Y, Qu X, et al., 'ITGB4 is essential for containing HDM-induced airway inflammation and airway hyperresponsiveness', Journal of Leukocyte Biology, 103 897-908 (2018) [C1]

©2018 Society for Leukocyte Biology Airway epithelial cells play a significant role in the pathogenesis of asthma. Although the structural and functional defects of airway epithel... [more]

©2018 Society for Leukocyte Biology Airway epithelial cells play a significant role in the pathogenesis of asthma. Although the structural and functional defects of airway epithelial cells have been postulated to increase asthma susceptibility and exacerbate asthma severity, the mechanism and implication of these defects remain uncertain. Integrin ß4 (ITGB4) is a structural adhesion molecule that is downregulated in the airway epithelium of asthma patients. In this study, we demonstrated that ITGB4 deficiency leads to severe allergy-induced airway inflammation and airway hyper-responsiveness (AHR) in mice. After house dust mite (HDM) challenge, epithelial cell-specific ITGB4-deleted mice showed increased lymphocyte, eosinophil, and neutrophil infiltration into lung compared with that of the wild-type mice. ITGB4 deficiency also resulted in increased expression of the Th2 cytokine IL-4, IL-13, and the Th17 cytokine IL-17A in the lung tissue and in the T cells after HDM challenge. The aggravated inflammation in ITGB4 defect mice was partly caused by enhanced disrupted epithelial barrier integrity after HDM stress, which induced the increased thymic stromal lymphopoietin secretion from airway epithelial cells. This study therefore demonstrates that ITGB4 plays a pivotal role in containing allergen-mediated lung inflammation and airway hyper-responsiveness in allergic asthma.

DOI 10.1002/JLB.3A1017-411RR
2018 Thi HN, Liu X, Su ZZ, Hsu AC-Y, Foster PS, Yang M, 'Potential Role of MicroRNAs in the Regulation of Antiviral Responses to influenza infection', FRONTIERS IN IMMUNOLOGY, 9 (2018) [C1]
DOI 10.3389/fimmu.2018.01541
Co-authors Alan Hsu, Paul Foster
2018 Nguyen TH, Maltby S, Tay HL, Eyers F, Foster PS, Yang M, 'Identification of IFN-¿ and IL-27 as Critical Regulators of Respiratory Syncytial Virus-Induced Exacerbation of Allergic Airways Disease in a Mouse Model', Journal of Immunology, 200 237-247 (2018) [C1]

Copyright © 2017 by The American Association of Immunologists, Inc. Respiratory syncytial virus (RSV) infection induces asthma exacerbations, which leads to worsening of clinical ... [more]

Copyright © 2017 by The American Association of Immunologists, Inc. Respiratory syncytial virus (RSV) infection induces asthma exacerbations, which leads to worsening of clinical symptoms and may result in a sustained decline in lung function. Exacerbations are the main cause of morbidity and mortality associated with asthma, and significantly contribute to asthma-associated healthcare costs. Although glucocorticoids are used to manage exacerbations, some patients respond to them poorly. The underlying mechanisms associated with steroid-resistant exacerbations remain largely unknown. We have previously established a mouse model of RSV-induced exacerbation of allergic airways disease, which mimics hallmark clinical features of asthma. In this study, we have identified key roles for macrophage IFN-¿ and IL-27 in the regulation of RSV-induced exacerbation of allergic airways disease. Production of IFN-¿ and IL-27 was steroid-resistant, and neutralization of IFN-¿ or IL-27 significantly suppressed RSV-induced steroid-resistant airway hyperresponsiveness and airway inflammation. We have previously implicated activation of pulmonary macrophage by TNF-a and/or MCP-1 in the mechanisms of RSV-induced exacerbation. Stimulation of pulmonary macrophages with TNF-a and/or MCP-1 induced expression of both IFN-¿ and IL-27. Our findings highlight critical roles for IFN-¿ and IL-27, downstream of TNF-a and MCP-1, in the mechanism of RSV-induced exacerbation. Thus, targeting the pathways that these factors activate may be a potential therapeutic approach for virus-induced asthma exacerbations.

DOI 10.4049/jimmunol.1601950
Citations Scopus - 1Web of Science - 1
Co-authors Paul Foster, Hock Tay, Steven Maltby
2018 Yuan J, Li B, Zhang N, Zhu H, Zhou L, Zhang L, Yang M, 'Clinical Implications of the BIM Deletion Polymorphism in Advanced Lung Adenocarcinoma Treated With Gefitinib', Clinical Lung Cancer, 19 e431-e438 (2018)

© 2018 Elsevier Inc. After investigating the clinical implications of BIM deletion polymorphism in advanced lung adenocarcinoma treated with gefitinib, we found that patients with... [more]

© 2018 Elsevier Inc. After investigating the clinical implications of BIM deletion polymorphism in advanced lung adenocarcinoma treated with gefitinib, we found that patients with BIM deletion genotypes had poor progression-free survival and overall survival after gefitinib treatment and were more likely to experience acquired gefitinib resistance, highlighting the clinical potential of the polymorphism in patient-tailored decisions during epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Background: Proapoptotic protein Bcl-2¿like 11 (BIM) is a crucial tumor suppressor gene in lung cancer development. A 2903-bp genomic deletion polymorphism is present in BIM intron 2, which alters RNA splicing and impairs the generation of the death-inducing isoform of BIM and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In the present study, we investigated the clinical implications of this genetic polymorphism in patients with advanced lung adenocarcinoma treated with gefitinib. Materials and Methods: After genotyping the BIM deletion polymorphism in 111 patients with stage IIIB or IV lung adenocarcinoma receiving gefitinib, the hazard ratio (HR) and 95% confidence interval (CI) for progression-free survival and overall survival were estimated using Cox proportional hazards models. Results: Possession of = 1 deletion allele of the BIM polymorphism was observed in 18.02% of the patients. The BIM deletion polymorphism was an independent indicator of a shorter PFS (7.5 months vs. 11.3 months; HR, 2.38; 95% CI, 1.30-4.34; P =.005) and shorter OS (9.9 months vs. 27.5 months; HR, 2.53; 95% CI, 1.37-4.65; P =.003). Additionally, patients carrying the BIM deletion allele were more likely to experience acquired gefitinib-resistant disease. Conclusion: Our results indicate that the BIM deletion polymorphism might be a promising germline biomarker for gefitinib treatment in Chinese patients with lung adenocarcinoma.

DOI 10.1016/j.cllc.2018.02.007
2017 Foster PS, Maltby S, Rosenberg HF, Tay HL, Hogan SP, Collison AM, et al., 'Modeling T

© 2017 John Wiley &amp; Sons A/S. Published by John Wiley &amp; Sons Ltd In this review, we highlight experiments conducted in our laboratories that have elucidated functional... [more]

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4+T-helper type-2 lymphocytes (TH2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical TH2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of TH2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote TH2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of TH2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches.

DOI 10.1111/imr.12549
Citations Scopus - 5Web of Science - 6
Co-authors Joerg Mattes, Adam Collison, Philip Hansbro, Hock Tay, Nicole Hansbro, Paul Foster, Steven Maltby, Gerard Kaiko
2017 Maltby S, Tay HL, Yang M, Foster PS, 'Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation', Respirology, 22 874-885 (2017) [C1]

© 2017 Asian Pacific Society of Respirology Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the major... [more]

© 2017 Asian Pacific Society of Respirology Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the majority of asthma patients, treatments for individuals with severe asthma are often ineffective. Mouse models are useful to identify mechanisms underlying disease pathogenesis and for the preclinical assessment of new therapies. In fact, existing mouse models have contributed significantly to our understanding of allergic/eosinophilic phenotypes of asthma and facilitated the development of novel targeted therapies (e.g. anti-IL-5 and anti-IgE). These therapies are effective in relevant subsets of severe asthma patients. Unfortunately, non-allergic/non-eosinophilic asthma, steroid resistance and disease exacerbation remain areas of unmet clinical need. No mouse model encompasses all features of severe asthma. However, mouse models can provide insight into pathogenic pathways that are relevant to severe asthma. In this review, as examples, we highlight models relevant to understanding steroid resistance, chronic tissue remodelling and disease exacerbation. Although these models highlight the complexity of the immune pathways that may underlie severe asthma, they also provide insight into new potential therapeutic approaches.

DOI 10.1111/resp.13052
Citations Scopus - 6Web of Science - 6
Co-authors Steven Maltby, Paul Foster, Hock Tay
2017 Zhu M, Yan C, Ren C, Huang X, Zhu X, Gu H, et al., 'Exome Array Analysis Identifies Variants in SPOCD1 and BTN3A2 That Affect Risk for Gastric Cancer', Gastroenterology, 152 2011-2021 (2017)

© 2017 AGA Institute Background &amp; Aims Several genetic variants have been associated with gastric cancer risk, although these account for only a fraction of cases of gastric c... [more]

© 2017 AGA Institute Background & Aims Several genetic variants have been associated with gastric cancer risk, although these account for only a fraction of cases of gastric cancer. We aimed to identify low-frequency and other genetic variants that determine gastric cancer susceptibility. Methods We performed exome array analysis of DNA in blood samples from 1113 patients with gastric cancer, collected at hospitals from 2006 to 2010 in China, and 1848 individuals without cancer (controls) undergoing physical examinations. Among 71,290 variants analyzed (including 25,784 common variants), 24 variants were selected and replicated in an analysis of DNA in blood samples from 4687 additional cases of gastric cancer and 5780 controls. We compared expression of candidate genes in tumor vs normal gastric tissues using data from TCGA and performed functional annotation analyses. An immortalized human gastric epithelial cell line (GES1) and 7 human gastric cancer lines were used to express transgenes, knock down gene expression (with small interfering RNAs), disrupt genes (using the CRISPR/Cas9 system), or assess expression of reporter constructs. We measured cell proliferation, colony formation, invasion, and migration, and assessed growth of xenograft tumors in nude mice. Results A low-frequency missense variant rs112754928 in the SPOC domain containing 1 gene (SPOCD1; encoding p.Arg71Trp), at 1p35.2, was reproducibly associated with reduced risk of gastric cancer (odds ratio, 0.56; P = 3.48 × 10¿8). SPOCD1 was overexpressed in gastric tumors, and knockout of SPOCD1 reduced gastric cancer cell proliferation, invasive activity, and migration, as well as growth of xenograft tumors in nude mice. We also associated the variant rs1679709 at 6p22.1 with reduced risk for gastric cancer (odds ratio, 0.80; P = 1.17 × 10¿13). The protective allele rs1679709-A correlated with the surrounding haplotype rs2799077-T¿rs2799079-C, which reduced the enhancer activity of this site to decrease expression of the butyrophilin subfamily 3 member A2 gene (BTN3A2). BTN3A2 is overexpressed in gastric tumors, and deletion of BTN3A2 inhibited proliferation, migration, and invasion of gastric cancer cells. Conclusions We have associated variants at 1p35.2 and 6p22.1 with gastric cancer risk, indicating a role for SPOCD1 and BTN3A2 in gastric carcinogenesis.

DOI 10.1053/j.gastro.2017.02.017
Citations Scopus - 8
2017 Wang Z, Dai J, Hu N, Miao X, Abnet CC, Yang M, et al., 'Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: Pooled results from two Chinese genome-wide association studies', Gut, 66 581-587 (2017)

© 2017, BMJ Publishing Group. All rights reserved. Objective: Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel ... [more]

© 2017, BMJ Publishing Group. All rights reserved. Objective: Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel association signals could be exploited by combining individual studies together, which will further elucidate the genetic susceptibility of non-cardia gastric cancer. Design: We conducted a meta-analysis of two published Chinese GWAS studies (2031 non-cardia gastric cancer cases and 4970 cancer-free controls) and followed by genotyping of additional 3564 cases and 4637 controls in two stages. Results: The overall meta-analysis revealed two new association signals. The first was a novel locus at 5q14.3 and marked by rs7712641 (per-allele OR=0.84, 95% CI 0.80 to 0.88; p=1.21×10-11). This single-nucleotide polymorphism (SNP) marker maps to the intron of the long non-coding RNA, lnc-POLR3G-4 (XLOC-004464), which we observed has lower expression in non-cardia gastric tumour compared with matched normal tissue (Pwilcoxon signed-rank=7.20×10-4). We also identified a new signal at the 1q22 locus, rs80142782 (per-allele OR=0.62; 95% CI 0.56 to 0.69; p=1.71×10-19), which was independent of the previously reported SNP at the same locus, rs4072037 (per-allele OR=0.74; 95% CI 0.69 to 0.79; p=6.28×10-17). Analysis of the new SNP conditioned on the known SNP showed that the new SNP remained genome-wide significant (Pconditional=3.47×10-8). Interestingly, rs80142782 has a minor allele frequency of 0.05 in East Asians but is monomorphic in both European and African populations. Conclusion: These findings add new evidence for inherited genetic susceptibility to non-cardia gastric cancer and provide further clues to its aetiology in the Han Chinese population.

DOI 10.1136/gutjnl-2015-310612
Citations Scopus - 11
2017 Ren Y, Shang J, Li J, Liu W, Zhang Z, Yuan J, Yang M, 'The long noncoding RNA PCAT-1 links the microRNA miR-215 to oncogene CRKL-mediated signaling in hepatocellular carcinoma', Journal of Biological Chemistry, 292 17939-17949 (2017)

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. The long non-coding RNA (lncRNA) PCAT-1 resides in the chromosome 8q24 cancer-risk locus and acts as a ... [more]

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. The long non-coding RNA (lncRNA) PCAT-1 resides in the chromosome 8q24 cancer-risk locus and acts as a vital oncogene during tumorigenesis and progression. However, how PCAT-1 is post-transcriptionally regulated, for example, by small ncRNAs, such as microRNAs (miRNAs) is largely unknown. Here, we report how miRNAs regulate PCAT-1 expression and also investigate the biological significance of this regulation in hepatocellular carcinoma (HCC). We found that miR-215, a P53-inducible miRNA, is a key regulator of PCAT-1 expression in HCC and identified an interaction between miR-215 and PCAT-1 in dual luciferase reporter gene assays. We also found that post-transcriptional silencing of PCAT-1 by miR-215 or PCAT-1 siRNAs significantly inhibited proliferation of HCC cells and, conversely, that inhibition of endogenous miR-215 up-regulated PCAT-1 expression and promoted cell viability. The tumor-suppressing role of miR-215 was further confirmed in an in vivo mouse HCC xenograft model. Of note, gene profiling assays suggested that the kinase CRK-like proto-oncogene, adaptor protein (CRKL), is a potential downstream target of the miR¿215¿PCAT-1 axis in HCC, and we demonstrated that CRKL silencing significantly suppresses cell proliferation. Taken together and considering the essential role of CRKL in cancer cells, we propose that the TP53¿miR-215¿PCAT-1¿CRKL axis might represent an important regulatory pathway in HCC. In summary, our results highlight the involvement of several ncRNAs in HCC and thus provide critical insights into the molecular pathways operating in this malignancy.

DOI 10.1074/jbc.M116.773978
Citations Scopus - 2
2017 Ren Y, Chen Y, Liang X, Lu Y, Pan W, Yang M, 'MiRNA-638 promotes autophagy and malignant phenotypes of cancer cells via directly suppressing DACT3', Cancer Letters, 390 126-136 (2017)

© 2017 Elsevier B.V. Dyregulation of autophagy is implicated in human cancers and the mechanism details remains largely unclear. Herein we report the regulatory role of miR-638 in... [more]

© 2017 Elsevier B.V. Dyregulation of autophagy is implicated in human cancers and the mechanism details remains largely unclear. Herein we report the regulatory role of miR-638 in autophagy of esophageal squamous cell carcinoma (ESCC) and breast cancer cells. We found that miR-638 overexpression promotes starvation- and rapamycin-induced autophagy. In ESCC and breast cancer cells, miR-638 acts as an oncogene and promotes cell proliferation, migration, as well as invasion in vitro and in vivo. In accordance with this, we observed significantly higher miR-638 expression in ESCC and breast cancer tissues compared to normal tissues. To further elucidate regulatory mechanisms of miR-638 in autophagy, we performed a computational nomination of its target genes through intersecting the results of multiple prediction algorithms. DACT3, a key regulator of Wnt/ß-catenin signaling, was predicted to be regulated by miR-638 by all programs and confirmed by experimental results. Depletion of DACT3 phenocopied effects of miR-638 overexpression, demonstrating its importance in autophagy. These results elucidate that the miR-638-DACT3 axis might be an important molecular pathway in controlling autophagy and tumorigenesis. Our data in clinical tissue samples highlight miR-638 and DACT3 as histological marker for cancer detection and their potentially therapeutic implications.

DOI 10.1016/j.canlet.2017.01.009
Citations Scopus - 15
2017 Pan W, Du J, Shi M, Jin G, Yang M, 'Short leukocyte telomere length, alone and in combination with smoking, contributes to increased risk of gastric cancer or esophageal squamous cell carcinoma', Carcinogenesis, 38 12-18 (2017)

© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. In humans, telomeres shorten along with ... [more]

© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. In humans, telomeres shorten along with division of somatic cells. Shortened telomere length might result in genomic instability and has been associated with several malignancies. However, the findings in different populations remain conflicting. Therefore, we assessed the association of telomere length in peripheral blood leukocytes with risk of gastric cancer (GC) or esophageal squamous cell carcinoma (ESCC) in a Chinese Han population. A total of 574 GC cases, 740 ESCC cases and 774 age- and sex-matched healthy controls were included in this analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. The GC or ESCC patients had significantly shorter relative telomere length (RTL) (median ± SD: GC: 1.20 ± 0.42; ESCC: 1.27 ± 0.48) than controls (1.41 ± 0.58). Four-fold increased GC risk (OR = 4.10, 95% CI = 2.78-6.05, P = 1.10 × 10-12) or 1.56-fold increased ESCC risk (95% CI = 1.12-2.18, P = 0.009) among subjects in the shortest quartile of telomere length was found compared with the highest quartile. We also observed a cumulative effect between short RTL and smoking in intensifying risk of GC (P = 4.50 × 10-9) or ESCC (P = 5.92 × 10-33). Moreover, there were cumulative effects between RTL, smoking and drinking in elevating risk of GC (Ptrend = 0.001) or ESCC (Ptrend = 1.57 × 10-32). Interestingly, RTL-related rs621559 and rs398652 genetic variants are significantly associated with GC risk. These results indicate that short RTL is involved in susceptibility to developing GC or ESCC, alone and in a gene-environment interaction manner. Short telomere length might be a potential molecular marker, in combination with lifestyle risk factors, to identify high-risk individuals.

DOI 10.1093/carcin/bgw111
2017 Shi M, Ma F, Liu J, Xing H, Zhu H, Yu J, Yang M, 'A functional BRCA1 coding sequence genetic variant contributes to prognosis of triple-negative breast cancer, especially after radiotherapy', Breast Cancer Research and Treatment, 166 109-116 (2017)

© 2017, Springer Science+Business Media, LLC. Purpose: As a subtype of breast cancer, triple-negative breast cancer (TNBC) shows poor¿prognosis and high heterogeneity. Precise ide... [more]

© 2017, Springer Science+Business Media, LLC. Purpose: As a subtype of breast cancer, triple-negative breast cancer (TNBC) shows poor¿prognosis and high heterogeneity. Precise identification of TNBC subgroups relevant to clinical prognosis is crucial in the design and administration of individualized treatments.¿This study aimed to evaluate¿the prognostic value of the functional¿BRCA1¿rs799917¿genetic variant in TNBC. Methods: Associations between the rs799917 polymorphism and progression risk were investigated after genotyping 370 TNBC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox regression. Results: We found that the rs799917T allele was associated with a significantly increased risk of disease¿progression¿and shortened progression-free survival time (PFS) (P = 0.001 for log-rank test). Notably,¿TNBC patients with the¿rs799917 CC genotype showed about 22 months prolonged PFS compared to the TT genotype after radiotherapy (HR 4.44, 95% CI 1.98¿9.93;¿P = 2.9¿×¿10-4). Additionally, in overweight patients, the mean PFS of the rs799917TT genotype was 10 months shorter than that of the CC genotype (HR 3.57, 95% CI 1.46¿8.73,¿P = 0.005). Conclusions: Our findings demonstrate that the functional¿BRCA1¿genetic variant contributes to prognosis of TNBC. Our study also highlights the clinical potential of this polymorphism in the screening of high-risk TNBC patients for recurrence and the possibility of patient-tailored decisions especially¿during¿radiotherapy.

DOI 10.1007/s10549-017-4395-1
2017 Li RQ, Ren Y, Liu W, Pan W, Xu FJ, Yang M, 'MicroRNA-mediated silence of onco-lncRNA MALAT1 in different ESCC cells via ligand-functionalized hydroxyl-rich nanovectors', Nanoscale, 9 2521-2530 (2017)

© The Royal Society of Chemistry. Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies worldwide. Long noncoding RNA (lncRNA) MALAT1 acts as an essenti... [more]

© The Royal Society of Chemistry. Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies worldwide. Long noncoding RNA (lncRNA) MALAT1 acts as an essential oncogene lncRNA (onco-lncRNA) in the development of ESCC. Down-regulation of onco-lncRNA MALAT1 mediated by microRNA-101 (miR-101) and microRNA-217 (miR-217) has been proved to effectively suppress ESCC. In this study, poly(glycidyl methacrylate)-based star-like polycations with flanking folic acid (FA) ligands and rich hydrophilic hydroxyl groups (denoted as s-PGEA-FA) were proposed as efficient nanovectors to deliver miR-101 and miR-217 for silencing onco-lncRNA MALAT1 in different ESCC cells. The inhibition of ESCC by s-PGEA-FA/miRNA nanocomplexes would be achieved via subsequently targeting onco-lncRNA MALAT1 in ESCC cells. To evaluate the ESCC tumor-suppressing efficacy mediated by s-PGEA-FA/miRNA nanocomplexes, a series of assays were carried out, including gene transfection, cell proliferation, cell migration, and cell invasion. The results revealed that s-PGEA-FA-mediated miR-101 and miR-217 delivery effectively inhibited ESCC development, indicating the s-PGEA-FA nanovector was promising for future ESCC therapy.

DOI 10.1039/c6nr09668a
Citations Scopus - 6
2017 Yuan J, Zhang N, Zhu H, Liu J, Xing H, Ma F, Yang M, 'CHST9 rs1436904 genetic variant contributes to prognosis of triple-negative breast cancer', Scientific Reports, 7 (2017)

© 2017 The Author(s). Triple-negative breast cancer (TNBC) refers to one aggressive histological subtype of breast cancer with high heterogeneity and poor prognosis after standard... [more]

© 2017 The Author(s). Triple-negative breast cancer (TNBC) refers to one aggressive histological subtype of breast cancer with high heterogeneity and poor prognosis after standard therapy. Lack of clearly established molecular mechanism driving TNBC progression makes personalized therapy more difficult. Thus, identification of genetic variants associated with TNBC prognosis will show clinic significance for individualized treatments. Our study is aimed to evaluate the prognostic value of the genome wide association study (GWAS)-identified CHST9 rs1436904 and AQP4 rs527616 genetic variants in our established early-stage TNBC sample database. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). CHST9 rs1436904G allele was significantly associated with decreased disease-free survival time (DFS) (8.5 months shorter in GG genotype carriers compared to TT genotype carriers, HR = 1.70, 95% CI = 1.03-2.81, P = 0.038). Stratified analyses showed an increased risk of cancer progression in CHST9 rs1436904G allele carriers harboring larger tumor (tumor size > 2 cm), without lymph-node metastasis, being premenopausal at diagnosis or with vascular invasion (P = 0.032, 0.017, 0.008 or 0.003). Our findings demonstrate that the GWAS-identified 18q11.2 CHST9 rs1436904 polymorphism significantly contributes to prognosis of early-stage TNBC, suggesting its clinical potential in the screening of high-risk TNBC patients for recurrence and the possibility of patient-tailored therapeutic decisions.

DOI 10.1038/s41598-017-12306-6
2016 Pan W, Zhou L, Ge M, Zhang B, Yang X, Xiong X, et al., 'Whole exome sequencing identifies lncRNA GAS8-AS1 and LPAR4 as novel papillary thyroid carcinoma driver alternations', Human Molecular Genetics, 25 1875-1884 (2016)

© The Author 2016. Published by Oxford University Press. All rights reserved. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, we know little ... [more]

© The Author 2016. Published by Oxford University Press. All rights reserved. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, we know little of mutational spectrum in the Chinese population. Thus, here we report the identification of somatic mutations for Chinese PTC using 402 tumor-normal pairs (Discovery: 91 pairs via exome sequencing; validation: 311 pairs via Sanger sequencing). We observed three distinct mutational signatures, evidently different from the two mutational signatures among Caucasian PTCs. Ten significantly mutated genes were identified, most previously uncharacterized. Notably, we found that long non-coding RNA (lncRNA) GAS8-AS1 is the secondary most frequently altered gene and acts as a novel tumor suppressor in PTC. As a mutation hotspot, the c.713A>G/714T>C dinucleotide substitution was found among 89.1% patients with GAS8-AS1 mutations and associated with advanced PTC disease (P = 0.009). Interestingly, the wild-type lncRNA GAS8-AS1 (A713T714) showed consistently higher capability to inhibit cancer cell growth compared to the mutated lncRNA (G713C714). Further studies also elucidated the oncogene nature of the G protein-coupled receptor LPAR4 and its c.872T>G (p.Ile291Ser) mutation in PTC malignant transformation. The BRAF c.1799T>A (p.Val600Glu) substitution was present in 59.0% Chinese PTCs, more frequently observed in patients with lymph node metastasis (P = 1.6 × 10-4). Together our study defines a exome mutational spectrum of PTC in the Chinese population and highlights lncRNA GAS8-AS1 and LPAR4 as potential diagnostics and therapeutic targets.

DOI 10.1093/hmg/ddw056
Citations Scopus - 14
2016 Yang X, Gao F, Ma F, Ren Y, Chen H, Liang X, et al., 'Association of the functional BCL-2 rs2279115 genetic variant and small cell lung cancer', Tumor Biology, 37 1693-1698 (2016)

© 2015, International Society of Oncology and BioMarkers (ISOBM). As a well-known oncogene, B cell lymphoma-2 (BCL-2) can promote cancer cell survival through preventing their apo... [more]

© 2015, International Society of Oncology and BioMarkers (ISOBM). As a well-known oncogene, B cell lymphoma-2 (BCL-2) can promote cancer cell survival through preventing their apoptosis. Several functional BCL-2 single nucleotide polymorphisms (SNPs), such as rs2279115, rs1801018, and rs1564483, have been identified and might contribute to cancer susceptibility. However, the involvement of these SNPs in small cell lung cancer (SCLC) was still unclear. As a result, we investigated associations between these three genetic variants and SCLC risk in a case-control design. Genotypes were determined in two independent case-control sets consisted of 520 SCLC patients and 1040 controls from two medical centers. Odds ratios (ORs) and 95¿% confidence intervals (CIs) were calculated utilizing unconditional logistic regression. We found that only BCL-2 rs2279115 genetic variant significantly contributed to decreased SCLC risk in Chinese Han populations, with the rs2279115 A allele as the protective allele. Stratified analyses of association between BCL2 rs2279115 SNP and SCLC risk indicated that the functional polymorphism was only significantly associated with decreased risk of the limited stage SCLC but not the extensive stage disease. Our results indicate that the BCL-2 rs2279115 genetic variant was associated with SCLC risk in Chinese populations and support the hypothesis that SNPs in regulatory regions of oncogenes might contribute to cancer susceptibility.

DOI 10.1007/s13277-015-3934-9
Citations Scopus - 2
2016 Xie R, Shi J, Cheng C, Yun F, Liu X, Tang P, et al., 'Synergistic effect of the combination of novel suberoylanilide hydroxamanic acid derivatives with cisplatin on anti-proliferation of human cancer cells', Medicinal Chemistry, 12 767-774 (2016)

© 2016 Bentham Science Publishers. A novel, green, and atom-economical boric acid catalyzed direct amidation without the use of any coupling agents for the preparation of suberoyl... [more]

© 2016 Bentham Science Publishers. A novel, green, and atom-economical boric acid catalyzed direct amidation without the use of any coupling agents for the preparation of suberoylanilide hydroxamic acid (SAHA) and SAHA-based inhibitors targeting anti-proliferation of cancer cells is provided. The new SAHA-based inhibitor B123, when used alone, exhibited higher anti-proliferative activities than SAHA or Cisplatin against a number of human cancer cells. We have examined the effect of combination of these SAHA-based inhibitors with Cisplatin. We found synergistic effects of the combination of SAHA-based inhibitors with Cisplatin over a wide range of concentrations against human liver cancer cells HepG2 and two human lung cancer cell lines H1299 and H460. This synergism leads up to 8-fold of dose reduction for Cisplatin in the combination with our synthesized inhibitor B123 against H1299.

DOI 10.2174/1573406412666160404125551
Citations Scopus - 3
2016 Li RQ, Wu W, Song HQ, Ren Y, Yang M, Li J, Xu FJ, 'Well-defined reducible cationic nanogels based on functionalized low-molecular-weight PGMA for effective pDNA and siRNA delivery', Acta Biomaterialia, 41 282-292 (2016)

© 2016 Acta Materialia Inc. Nucleic acid-based gene therapy is a promising treatment option to cure numerous intractable diseases. For non-viral gene carriers, low-molecular-weigh... [more]

© 2016 Acta Materialia Inc. Nucleic acid-based gene therapy is a promising treatment option to cure numerous intractable diseases. For non-viral gene carriers, low-molecular-weight polymeric vectors generally demonstrate poor transfection performance, but benefit their final removals from the body. Recently, it was reported that aminated poly(glycidyl methacrylate) (PGMA) is one potential gene vector. Based on ethylenediamine (ED)-functionalized low-molecular-weight PGMA (denoted by PGED), a flexible strategy was herein proposed to design new well-defined reducible cationic nanogels (denoted by PGED-NGs) with friendly crosslinking reagents for highly efficient nucleic acid delivery. a-Lipoic acid (LA), one natural antioxidant in human body, was readily introduced into ED-functionalized PGMA and crosslinked to produce cationic PGED-NGs with plentiful reducible lipoyl groups. PGED-NGs could effectively complex plasmid DNA (pDNA) and short interfering RNA (siRNA). Compared with pristine PGED, PGED-NGs exhibited much better performance of pDNA transfection. PGED-NGs also could efficiently transport MALAT1 siRNA (siR-M) into hepatoma cells and significantly suppressed the cancer cell proliferation and migration. The present work indicated that reducible cationic nanogels involving LA crosslinking reagents are one kind of competitive candidates for high-performance nucleic acid delivery systems. Statement of Significance Recently, the design of new types of high-performance nanoparticles is of great significance in delivering therapeutics. Nucleic acid-based therapy is a promising treatment option to cure numerous intractable diseases. A facile and straightforward strategy to fabricate safe nucleic acid delivery nanovectors is highly desirable. In this work, based on ethylenediamine-functionalized low-molecular-weight poly(glycidyl methacrylate), a flexible strategy was proposed to design new well-defined reducible cationic nanogels (denoted by PGED-NGs) with a-Lipoic acid, one friendly crosslinking reagent, for highly efficient nucleic acid delivery. Such PGED-NGs possess plentiful reducible lipoyl groups, effectively encapsulated pDNA and siRNA and exhibited excellent abilities of nucleic acid delivery. The present work indicated that reducible cationic nanogels involving a-lipoic acid crosslinking reagents are one kind of competitive candidates for high-performance nucleic acid delivery systems.

DOI 10.1016/j.actbio.2016.06.006
Citations Scopus - 11
2016 Zhou L, Fu G, Wei J, Shi J, Pan W, Ren Y, et al., 'The identification of two regulatory ESCC susceptibility genetic variants in the TERT-CLPTM1L loci', Oncotarget, 7 5495-5506 (2016)

The chromosome 5p15.33 TERT-CLPTM1L region has been identified by genome-wide association studies as a susceptibility locus of multiple malignancies. However, the involvement of t... [more]

The chromosome 5p15.33 TERT-CLPTM1L region has been identified by genome-wide association studies as a susceptibility locus of multiple malignancies. However, the involvement of this locus in esophageal squamous cell carcinoma (ESCC) development is still largely unclear. We fine-mapped the TERT-CLPTM1L region through genotyping 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) using a two stage case-control strategy. After analyzing 2098 ESCC patients and frequency-matched 2150 unaffected controls, we found that rs2853691, rs2736100 and rs451360 genetic polymorphisms are significantly associated with ESCC risk in Chinese (all P < 0.05). Reporter gene assays indicated that the ESCC susceptibility SNP rs2736100 locating in a potential TERT intronic promoter has a genotype-specific effect on TERT expression. Similarly, the CLPTM1L rs451360 SNP also showed allelic impacts on gene expression. After measuring TERT and CLPTM1L expression in sixty-six pairs of esophageal cancer and normal tissues, we observed that the rs2736100 G risk allele carriers showed elevated oncogene TERT expression. Also, subjects with the rs451360 protective T allele had much lower oncogene CLPTM1L expression than those with G allele in tissue specimens. Results of these analyses underline the complexity of genetic regulation of telomere biology and further support the important role of telomerase in carcinogenesis. Our data also support the involvement of CLPTM1L in ESCC susceptibility.

DOI 10.18632/oncotarget.6747
Citations Scopus - 9
2016 Nguyen TH, Maltby S, Simpson JL, Eyers F, Baines KJ, Gibson PG, et al., 'TNF-a and macrophages are critical for respiratory syncytial virus-induced exacerbations in a mouse model of allergic airways disease', Journal of Immunology, 196 3547-3558 (2016) [C1]

Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation... [more]

Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation, we established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation after allergen sensitization and challenge. RSV infection of OVA-sensitized/challenged BALB/c mice resulted in significantly increased airway hyperresponsiveness (AHR) and macrophage and neutrophil lung infiltration. Exacerbation was accompanied by increased levels of inflammatory cytokines (including TNF-a, MCP-1, and keratinocyte-derived protein chemokine [KC]) compared with uninfected OVA-treated mice or OVA-treated mice exposed to UV-inactivated RSV. Dexamethasone treatment completely inhibited all features of allergic disease, including AHR and eosinophil infiltration, in uninfected OVAsensitized/challenged mice. Conversely, dexamethasone treatment following RSV-induced exacerbation only partially suppressed AHR and failed to dampen macrophage and neutrophil infiltration or inflammatory cytokine production (TNF-a, MCP-1, and KC). This mimics clinical observations in patients with exacerbations, which is associated with increased neutrophils and often poorly responds to corticosteroid therapy. Interestingly, we also observed increased TNF-a levels in sputum samples from patients with neutrophilic asthma. Although RSV-induced exacerbation was resistant to steroid treatment, inhibition of TNF-a and MCP-1 function or depletion of macrophages suppressed features of disease, including AHR and macrophage and neutrophil infiltration. Our findings highlight critical roles for macrophages and inflammatory cytokines (including TNF-a and MCP-1) in viral-induced exacerbation of asthma and suggest examination of these pathways as novel therapeutic approaches for disease management.

DOI 10.4049/jimmunol.1502339
Citations Scopus - 11Web of Science - 11
Co-authors Jodie Simpson, Paul Foster, Peter Gibson, Steven Maltby, Katherine Baines
2016 Xiang Y, Eyers F, Herbert C, Tay HL, Foster PS, Yang M, 'MicroRNA-487b is a negative regulator of macrophage activation by targeting IL-33 production', Journal of Immunology, 196 3421-3428 (2016) [C1]

Copyright © 2016 by The American Association of Immunologists, Inc. MicroRNAs (miRNAs) are short noncoding RNAs that regulate a broad spectrum of biological processes, including i... [more]

Copyright © 2016 by The American Association of Immunologists, Inc. MicroRNAs (miRNAs) are short noncoding RNAs that regulate a broad spectrum of biological processes, including immune responses. Although the contributions of miRNAs to the function of immune cells are beginning to emerge, their specific roles remain largely unknown. IL-33 plays an important role in macrophage activation for innate host defense and proinflammatory responses. In this study, we report that miR-487b can suppress the levels of mRNA and protein for IL-33 during the differentiation of bone marrow-derived macrophages (BMDMs). This results in inhibition of IL-33-induced expression of Ag-presenting and costimulatory molecules and proinflammatory mediators. A luciferase assay showed that miR-487b binds to the IL-33 39-untranslated region. We also confirmed that IL-33 directly promotes the activation of BMDMs by increasing the expression of MHC class I, MHC class II, CD80/CD86, and inducible NO synthase (iNOS) in a dose-dependent manner. Exposure of BMDMs to the TLR4 ligand, LPS, decreased miR-487b expression, increased IL-33 transcript levels, and induced the production of proinflammatory mediators (e.g., iNOS, IL-1b, IL-6, and TNF-a). Treatment with a specific inhibitor of miR-487b function also resulted in increased levels of IL-33 mRNA, which augmented LPS-induced expression of these inflammatory mediators in macrophages. Collectively, our results indicate that miR-487b plays a negative regulatory role in macrophages by controlling the levels of IL-33 transcript and protein to fine-tune innate immune host defense and proinflammatory responses of these cells. Thus, miR-487b plays an important role in the regulation of macrophage homeostasis and activation by targeting IL-33 transcripts.

DOI 10.4049/jimmunol.1502081
Citations Scopus - 14Web of Science - 16
Co-authors Paul Foster, Hock Tay
2016 Zhuang J, Tang X, Du Z, Yang M, Zhou Y, 'Prediction of biomarkers of therapeutic effects of patients with lung adenocarcinoma treated with gefitinib based on progression-free-survival by metabolomic fingerprinting', Talanta, 160 636-644 (2016)

© 2016 Elsevier B.V. Lung carcinoma is one of the most frequently diagnosed malignancy and threats human life and health. In clinical practice, gefitinib, one of the most well-kno... [more]

© 2016 Elsevier B.V. Lung carcinoma is one of the most frequently diagnosed malignancy and threats human life and health. In clinical practice, gefitinib, one of the most well-known epidermal growth factor receptor tyrosine kinase inhibitors, was frequently used in the treatment of non-small cell lung carcinoma. However, this drug is not useful for all non-small cell patients. In this study, the biomarkers were found out to predict the therapeutic effects of gefitinib for lung carcinoma patients. Serum samples were collected from patients with advanced lung adenocarcinoma. The ultra-high performance liquid chromatography (UHPLC)-quadrupole-time of flight mass spectrometry (Q-TOF MS) was conducted to obtain the metabolic data for each patient. Partial least squares-discriminate analysis (PLS-DA) was performed to indicate the differences between metabolites of patients, and Cox proportional hazards regression analysis was used to eliminate the interference of the patient's gender, age, smoking history and disease stage. Thus, differential biomarkers were found. The combination of these biomarkers was statistically significant predictors based on progression-free survival. If these biomarkers can be further confirmed by the clinic, it could suggest the proper therapeutic schedule, and help to reduce patients¿ economic burden and medication side effects.

DOI 10.1016/j.talanta.2016.08.007
Citations Scopus - 2
2016 Guo H, Yang M, 'Erratum to The interaction of APEX1 variant with polycyclic aromatic hydrocarbons on increasing chromosome damage and lung cancer risk among male Chinese. [Mol Carcinog (2015), 54(S1), E103-E111.]', Molecular Carcinogenesis, 55 1124-1124 (2016)
DOI 10.1002/mc.22482
2016 Ren Y, Li RQ, Cai YR, Xia T, Yang M, Xu FJ, 'Effective Codelivery of lncRNA and pDNA by Pullulan-Based Nanovectors for Promising Therapy of Hepatocellular Carcinoma', Advanced Functional Materials, 26 7314-7325 (2016)

© 2016 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim Hepatocellular carcinoma (HCC) is one of the most common cancers. Maternally expressed gene 3 (MEG3, one kind of long nonco... [more]

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Hepatocellular carcinoma (HCC) is one of the most common cancers. Maternally expressed gene 3 (MEG3, one kind of long noncoding RNA [lncRNA]) can act as a tumor suppressor and regulate P53 target gene expression. However, lncRNA MEG3 demonstrates relatively low or no expression in human HCC. This study provides a promising concept to codeliver lncRNA and pDNA for cancer therapy. As proof-of-concept, the pcDNA-MEG3 and pcDNA-P53 plasmids-condensed nanocomplexes with the liver-targeting polycation gene vector, pullulan-based ethanolamine-modified poly(glycidyl methacrylate) (denoted as PuPGEA), are proposed to codeliver lncRNA and pDNA to treat HCC. Pullulan-containing nanovectors are shown to be able to effectively mediate gene delivery in liver cells. To assess gene delivery performances of PuPGEA, a series of assays such as in vitro gene transfection, HCC cell proliferation, colony formation, migration, matrigel transwell assays, and in vivo xenograft animal models are carried out. The codelivery system with PuPGEA/(MEG3+P53) nanocomplexes demonstrates additive effects in suppressing HCC compared to PuPGEA/MEG3 or PuPGEA/P53 nanocomplexes alone. These results suggest that codelivery of lncRNA and pDNA by polycation nanovectors is a promising method to treat cancers.

DOI 10.1002/adfm.201603041
Citations Scopus - 13
2016 Wang WT, Li Z, Shi M, Zhu H, Xiong X, Shang J, et al., 'Association of the GLB1 rs4678680 genetic variant with risk of HBV-related hepatocellular carcinoma', Oncotarget, 7 56501-56507 (2016)

Accumulated evidences demonstrated that GLB1 is involved in cell senescence and cancer development. The GLB1 rs4678680 single nucleotide polymorphism (SNP) has been identified as ... [more]

Accumulated evidences demonstrated that GLB1 is involved in cell senescence and cancer development. The GLB1 rs4678680 single nucleotide polymorphism (SNP) has been identified as a hepatocellular carcinoma (HCC) susceptibility polymorphism by a genome-wide association study in Korean population previously. However, little or nothing was known about its involvement and functional significance in hepatitis B viruses (HBV)-related HCC in Chinese. Therefore, we investigated the association between the GLB1 rs4678680 SNP and HBV-related HCC risk as well as its biological function in vivo. Genotypes were determined in two independent case-control sets from two medical centers of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The potential regulation role the rs4678680 genetic variant on GLB1 expression was examined with HCC and normal liver tissues. We found that The rs4678680 G allele was showed to be risk allele; individuals with the TG genotype had an OR of 1.51 (95% CI = 1.10-2.07, P = 0.010, Shandong set) or 1.49 (95% CI = 1.11-1.99, P = 0.008, Jiangsu set) for developing HBV-related HCC, respectively, compared with individuals with the TT genotype. This association was more pronounced in males, individuals aged older than 57 years and drinkers (all P < 0.05). In the genotype-phenotype correlation analyses of fifty-six human liver tissue samples, rs4678680 TG or GG was associated with a statistically significant increase of GLB1 mRNA expression (P < 0.05). Our data indicated that the GLB1 rs4678680 SNP contributes to susceptibility to develop HBV-related HCC, highlighting the involvement of GLB1 and cell senescence in etiology of HCC.

DOI 10.18632/oncotarget.10963
Citations Scopus - 3
2016 Yang M, Wang H, Zhou M, Liu W, Kuang P, Liang H, Yuan Q, 'The natural compound sulforaphene, as a novel anticancer reagent, targeting PI3K-AKT signaling pathway in lung cancer', Oncotarget, 7 76656-76666 (2016)

Lung cancer is one of the leading causes of cancer death worldwide. Isothiocyanates from cruciferous vegetables been shown to possess anticarcinogenic activities in lung malignanc... [more]

Lung cancer is one of the leading causes of cancer death worldwide. Isothiocyanates from cruciferous vegetables been shown to possess anticarcinogenic activities in lung malignances. We previously found sulforaphene (4-methylsufinyl-3-butenyl isothiocyanate, SFE), one new kind of isothiocyanates, existing in a relative high abundance in radish seeds. An efficient methodology based on macroporous resin and preparative high-performance liquid chromatography was developed to isolate SFE in reasonably large quantities, high purity and low cost. However, it is still largely unclear whether SFE could function as an antineoplastic compound, especially in lung cancer. In this study, we systematically investigated the anti-cancer effects of SFE in vitro as well as its possible underling molecular mechanisms in lung cancer. The acute toxicity tests and pharmacokinetics tests for SFE were performed to evaluate its drugability in mice. Also, we evaluated the in vivo anti-cancer effects of SFE using nude Balb/C mice with lung cancer xenograft. SFE can induce apoptosis of multiple lung cancer celllines and, thus, inhibited cancer cell proliferation. Lung cancer cells treated with SFE exhibit significant inhibition of the PI3K-AKT signaling pathway, including depressed PTEN expression and inhibition of AKT phosphoralation. At well-tolerated doses, administration of SFE to mice bearing lung cancer xenografts leads to significant inhibitions of tumor growth. In summary, our work identifies SFE as a novel natural broad-spectrum small molecule inhibitor for lung cancer.

DOI 10.18632/oncotarget.12307
Citations Scopus - 4
2016 Yang M, Ren M, Qu Y, Teng W, Wang Z, Li H, Yuan Q, 'Sulforaphene inhibits hepatocellular carcinoma through repressing keratin 8 and activating anoikis', RSC Advances, 6 70326-70334 (2016)

© The Royal Society of Chemistry 2016. Sulforaphene (SFE), a natural isothiocyanate, extracted from radish seeds is forcefully associated with cancer prevention. Nonetheless, the ... [more]

© The Royal Society of Chemistry 2016. Sulforaphene (SFE), a natural isothiocyanate, extracted from radish seeds is forcefully associated with cancer prevention. Nonetheless, the mechanism responsible for SFE-induced cell death is not understood. In the present study, one of the anti-cancer mechanisms of SFE was clarified in hepatocellular carcinoma. SFE exerted cytotoxicity in a concentration-dependent manner and led to apoptotic cell death in HepG2 and SMMC7721. After SFE treatment, a large number of spherical cells were suspended in the medium, and the phenomenon was not associated with EMT. We speculated that the phenomenon should be connected with anoikis. A proteomics study revealed that levels of some proteins including Keratin 8 (KRT8) and Enolase1 (ENO1), etc. were changed in SFE treated cells compared to an untreated control. We had further confirmed that SFE reduced the expression of Keratin 8 and Keratin 18 (K8/18) typically co-expressed as the primary keratin pair with western blotting. What's more, K8/18 loss increased the level of Fas and decreased the level of the inhibitory protein cFLIP. Interestingly, we showed that SFE-treated cells lost cell-matrix interactions without inducing metastasis and increased the apoptosis ratio in a suspension culture model as well as the K8/18 siRNA-treated cell. Taken together, these findings suggest that keratin 8 plays a role in mediating SFE-induced Fas-related death in hepatocellular carcinoma. And our findings present the first evidence that SFE decreased the resistance to anoikis in liver cancer cell lines.

DOI 10.1039/c6ra11176a
Citations Scopus - 1
2016 Ge M, Shi M, An C, Yang W, Nie X, Zhang J, et al., 'Functional evaluation of TERT-CLPTM1L genetic variants associated with susceptibility of papillary thyroid carcinoma', Scientific Reports, 6 (2016)

TERT is the catalytic subunit of telomerase which plays an essential part in cellular immortality by maintaining telomere integrity. TERT is commonly over-expressed in human malig... [more]

TERT is the catalytic subunit of telomerase which plays an essential part in cellular immortality by maintaining telomere integrity. TERT is commonly over-expressed in human malignancies, indicating its key role in cell transformation. The chromosome 5p15.33 TERT-CLPTM1L region has been associated with susceptibility of multiple cancers via a genome-wide association approach. However, the involvement of this locus in papillary thyroid carcinoma (PTC) etiology is still largely unknown. We analyzed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) of the TERT-CLPTM1L region in a two stage case-control design. After genotyping 2300 PTC patients and frequency-matched 2300 unaffected controls, we found that TERT rs2736100 genetic variant is significantly associated with elevated PTC risk. Ex vivo reporter gene assays indicated that the PTC susceptibility rs2736100 polymorphism locating in a potential TERT intronic enhancer has a genotype-specific effect on TERT expression. Correlations between rs2736100 genotypes and tissue-specific TERT expression supported the regulatory function of this genetic variant in vivo. Our data demonstrated that the functional TERT rs2736100 SNP as a novel genetic component of PTC etiology. This study, together with recent studies in other cancers, unequivocally establishes an essential role of TERT in cancers.

DOI 10.1038/srep26037
Citations Scopus - 7
2016 Shi M, Xia J, Xing H, Yang W, Xiong X, Pan W, et al., 'The Sp1-mediaded allelic regulation of MMP13 expression by an ESCC susceptibility SNP rs2252070', Scientific Reports, 6 (2016)

Metallopeptidase 13 (MMP13), a well-known and highly regulated zinc-dependent MMP collagenase, plays a crucial part in development and progression of esophageal squamous cell carc... [more]

Metallopeptidase 13 (MMP13), a well-known and highly regulated zinc-dependent MMP collagenase, plays a crucial part in development and progression of esophageal squamous cell carcinoma (ESCC). Therefore, we examined associations between ESCC susceptibility and four haplotype-tagging single nucleotide polymorphisms (htSNPs) using a two stage case-control strategy. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed by logistic regression model. After analyzing 1588 ESCC patients and frequency-matched 1600 unaffected controls, we found that MMP13 rs2252070 G > A genetic polymorphism is significantly associated with ESCC risk in Chinese Han populations (GA: OR = 0.63, 95% CI = 0.54-0.74, P = 1.7 × 10-6, AA: OR = 0.73, 95% CI = 0.66-0.81, P = 1.8 × 10-6). Interestingly, the rs2252070 G-to-A change was shown to diminish a Sp1-binding site in ESCC cells. Reporter gene assays indicated that the rs2252070 A allele locating in a potential MMP13 promoter has low promoter activities. After measuring MMP13 gene expression in sixty-six pairs of esophageal cancer and normal tissues, we observed that the rs2252070 A protective allele carriers showed decreased oncogene MMP13 expression. Results of these analyses underline the support of the notion that MMP13 might function as a key oncogene in esophageal carcinogenesis.

DOI 10.1038/srep27013
Citations Scopus - 5
2016 Zhu H, Lv Z, An C, Shi M, Pan W, Zhou L, et al., 'Onco-lncRNA HOTAIR and its functional genetic variants in papillary thyroid carcinoma', Scientific Reports, 6 (2016)

© The Author(s) 2016. The role of long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) and its functional single nucleotide polymorphisms (SNPs) in papillary thyroid ... [more]

© The Author(s) 2016. The role of long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) and its functional single nucleotide polymorphisms (SNPs) in papillary thyroid carcinoma (PTC) is still largely unclear. Therefore, we investigated the involvement of lncRNA HOTAIR and its three haplotype-tagging SNPs (htSNPs) in PTC. There was higher expression of HOTAIR in PTC tissues compared to normal tissues. A series of gain-loss assays demonstrated that HOTAIR acts as a PTC oncogene via promoting tumorigenic properties of PTC cells. Additionally, the functional HOTAIR rs920778 genetic variant was a PTC susceptibility SNP. Subjects with the HOTAIR rs920778 TT genotype had an odds ratio (OR) of 1.88, 1.25 and 1.61 (P = 6.0 × 10-6, P = 0.028 and P = 3.2 × 10-5) for developing PTC in Shandong, Jiangsu and Jilin case-control sets compared with subjects with the CC genotype. This statistically significant associations were only found between the rs920778 genetic polymorphism and PTC risk in females but not in males. The allele-specific regulation on HOTAIR expression by the rs920778 SNP was confirmed both in vitro and in vivo. Our results demonstrate that functional SNPs influencing lncRNA regulation may explain a part of PTC genetic basis.

DOI 10.1038/srep31969
Citations Scopus - 24
2016 Zhou H, Zhang J, Eyers F, Xiang Y, Herbert C, Tay HL, et al., 'Identification of the microRNA networks contributing to macrophage differentiation and function', Oncotarget, 7 28806-28820 (2016) [C1]

Limited evidence is available about the specific miRNA networks that regulate differentiation of specific immune cells. In this study, we characterized miRNA expression and associ... [more]

Limited evidence is available about the specific miRNA networks that regulate differentiation of specific immune cells. In this study, we characterized miRNA expression and associated alterations in expression with putative mRNA targets that are critical during differentiation of macrophages. In an effort to map the dynamic changes in the bone marrow (BM), we profiled whole BM cultures during differentiation into macrophages. We identified 112 miRNAs with expression patterns that were differentially regulated 5-fold or more during BMDM development. With TargetScan and MeSH databases, we identified 1267 transcripts involved in 30 canonical pathways linked to macrophage biology as potentially regulated by these specific 112 miRNAs. Furthermore, by employing miRanda and Ingenuity Pathways Analysis (IPA) analysis systems, we identified 18 miRNAs that are temporally linked to the expression of CSF1R, CD36, MSR1 and SCARB1; 7 miRNAs linked to the regulation of the transcription factors RUNX1 and PU.1, and 14 miRNAs target the nuclear receptor PPARa and PPAR¿. This novel information provides an important reference resource for further study of the functional links between miRNAs and their target mRNAs for the regulation of differentiation and function of macrophages.

DOI 10.18632/oncotarget.8933
Citations Scopus - 1Web of Science - 2
Co-authors Paul Foster, Hock Tay
2016 Yang X, Yu D, Ren Y, Wei J, Pan W, Zhou C, et al., 'Integrative Functional Genomics Implicates EPB41 Dysregulation in Hepatocellular Carcinoma Risk', American Journal of Human Genetics, 99 275-286 (2016)

© 2016 American Society of Human Genetics Genome-wide association studies (GWASs) have provided many insights into cancer genetics. However, the molecular mechanisms of many susce... [more]

© 2016 American Society of Human Genetics Genome-wide association studies (GWASs) have provided many insights into cancer genetics. However, the molecular mechanisms of many susceptibility SNPs defined by GWASs in cancer heritability and in promoting cancer risk remain elusive. New research strategies, including functional evaluations, are warranted to systematically explore truly causal genetic variants. In this study, we developed an integrative functional genomics methodology to identify cancer susceptibility SNPs in transcription factor-binding sites across the whole genome. Employing integration of functional genomic data from c-Myc cistromics, 1000 Genomes, and the TRANSFAC matrix, we successfully annotated 12 SNPs present in the c-Myc cistrome with properties consistent with modulating c-Myc binding affinity in hepatocellular carcinoma (HCC). After genotyping these 12 SNPs in 1,806 HBV-related HCC case subjects and 1,708 control subjects, we identified a HCC susceptibility SNP, rs157224G>T, in Chinese populations (T allele: odds ratio = 1.64, 95% confidence interval = 1.32¿2.02; p = 5.2¿× 10-6). This polymorphism leads to HCC predisposition through modifying c-Myc-mediated transcriptional regulation of EPB41, with the risk rs157224T allele showing significantly decreased gene expression. Based on cell proliferation, wound healing, and transwell assays as well as the mouse xenograft model, we identify EPB41 as a HCC susceptibility gene in¿vitro and in¿vivo. Consistent with this notion, we note that EPB41 expression is significantly decreased in HCC tissue specimens, especially in portal vein metastasis or intrahepatic metastasis, compared to normal tissues. Our results highlight the involvement of regulatory genetic variants in HCC and provide pathogenic insights of this malignancy via a genome-wide approach.

DOI 10.1016/j.ajhg.2016.05.029
Citations Scopus - 8
2016 Yang M, Teng W, Qu Y, Wang H, Yuan Q, 'Sulforaphene inhibits triple negative breast cancer through activating tumor suppressor Egr1', Breast Cancer Research and Treatment, 158 277-286 (2016)

© 2016, Springer Science+Business Media New York. Sulforaphene (SFE, 4-methylsufinyl-3-butenyl isothiocyanate) is a member of isothiocyanates, which is derived from radish seeds. ... [more]

© 2016, Springer Science+Business Media New York. Sulforaphene (SFE, 4-methylsufinyl-3-butenyl isothiocyanate) is a member of isothiocyanates, which is derived from radish seeds. It has shown that multiple isothiocyanates, such as sulforaphane, can effectively inhibit cancer cell proliferation in vitro and in vivo. However, it is still largely unknown if SFE could impact breast cancer. In this study, we investigated the anticancer effects of SFE on triple negative breast cancer (TNBC) via a series of in vitro and in vivo assays. We found that SFE can significantly inhibit cell proliferation in multiple TNBC cell lines through inducing G2/M phase arrest as well as cell apoptosis. Nude mice xenograft assays support the anti-TNBC role of SFE in vivo. Interestingly, SFE can repress expression of cyclinB1, Cdc2, and phosphorylated Cdc2, and, then, induced G2/M phase arrest of TNBC cells. To identify SFE target genes, we detected genome-wide gene expression changes through gene expression profiling and observed 27 upregulated and 18 downregulated genes in MDA-MB-453 cells treated with SFE. Among these genes, Egr1 was successfully validated as a consistently activated gene after SFE treatment in TNBC MDA-MB-453 and MDA-MB-436 cells. Egr1 overexpression inhibited proliferation of TNBC cells. However, Egr1 knockdown using siRNAs significantly promoted TNBC cell growth, indicating the tumor suppressor nature of Egr1. In sum, we for the first time found that SFE might be a potential anti-TNBC natural compound and its antiproliferation effects might be mediated by tumor suppressor Egr1.

DOI 10.1007/s10549-016-3888-7
Citations Scopus - 6
2016 Pan W, Liu L, Wei J, Ge Y, Zhang J, Chen H, et al., 'A functional lncRNA HOTAIR genetic variant contributes to gastric cancer susceptibility', Molecular Carcinogenesis, 55 90-96 (2016)

© 2016 Wiley Periodicals, Inc. Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) acts as an oncogene in gastric cancer development. HOTAIR could induce genome-wide... [more]

© 2016 Wiley Periodicals, Inc. Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) acts as an oncogene in gastric cancer development. HOTAIR could induce genome-wide retargeting of polycomb-repressive complex 2, trimethylates histone H3 lysine-27 (H3K27me3) and deregulation of multiple downstream genes. Additionally, as the ceRNA of miR-331-3p, HOTAIR may modulate HER2 deregulation in gastric cancer cells. We hypothesized that the functional single nucleotide polymorphisms (SNP) in HOTAIR may affect HOTAIR expression and/or its function and, thus, gastric cancer risk. We examined the association between three haplotype-tagging SNPs (htSNP) across the whole HOTAIR locus and gastric cancer risk as well as the functional relevance of a gastric cancer susceptibility SNP rs920778. Genotypes were determined in two independent hospital-based case-control sets that consisted of 800 gastric cancer patients and 1600 controls. The allele-specific regulation on HOTAIR expression by the rs920778 SNP was examined in vitro and in vivo. We found that the HOTAIR rs920778 TT carriers had a 1.66- and 1.87-fold increased gastric cancer risk in Jinan and Huaian populations compared with the CC carriers (P=4.2×10-4and 6.5×10-5). During inspecting functional relevance of the rs920778 SNP, we observed an allelic regulation of rs920778 on HOTAIR expression in both gastric cancer cell lines and tissue samples, with higher HOTAIR expression among T allele carriers. These findings elucidate that functional genetic variants influencing lncRNA expression may explain a portion of gastric cancer genetic basis.

DOI 10.1002/mc.22261
Citations Scopus - 54
2016 Thi HN, Maltby S, Eyers F, Foster PS, Yang M, 'Bromodomain and Extra Terminal (BET) Inhibitor Suppresses Macrophage-Driven Steroid-Resistant Exacerbations of Airway Hyper-Responsiveness and Inflammation', PLOS ONE, 11 (2016) [C1]
DOI 10.1371/journal.pone.0163392
Citations Scopus - 4Web of Science - 5
Co-authors Paul Foster, Steven Maltby
2015 Tay HL, Kaiko GE, Plank M, Li J, Maltby S, Essilfie A-T, et al., 'Correction: Antagonism of miR-328 Increases the Antimicrobial Function of Macrophages and Neutrophils and Rapid Clearance of Non-typeable Haemophilus Influenzae (NTHi) from Infected Lung.', PLoS pathogens, 11 e1004956 (2015) [O1]
DOI 10.1371/journal.ppat.1004956
Citations Scopus - 1
Co-authors Joerg Mattes, Philip Hansbro, Paul Foster, Gerard Kaiko, Steven Maltby, Hock Tay
2015 Li JJ, Tay HL, Maltby S, Xiang Y, Eyers F, Hatchwell L, et al., 'MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity', Journal of Allergy and Clinical Immunology, 136 462-473 (2015) [C1]

© 2015 American Academy of Allergy, Asthma &amp; Immunology. Background Steroid-resistant asthma is a major clinical problem that is linked to activation of innate immune cells.... [more]

© 2015 American Academy of Allergy, Asthma & Immunology. Background Steroid-resistant asthma is a major clinical problem that is linked to activation of innate immune cells. Levels of IFN-¿ and LPS are often increased in these patients. Cooperative signaling between IFN-¿/LPS induces macrophage-dependent steroid-resistant airway hyperresponsiveness (AHR) in mouse models. MicroRNAs (miRs) are small noncoding RNAs that regulate the function of innate immune cells by controlling mRNA stability and translation. Their role in regulating glucocorticoid responsiveness and AHR remains unexplored. Objective IFN-¿ and LPS synergistically increase the expression of miR-9 in macrophages and lung tissue, suggesting a role in the mechanisms of steroid resistance. Here we demonstrate the role of miR-9 in IFN-¿/LPS-induced inhibition of dexamethasone (DEX) signaling in macrophages and in induction of steroid-resistant AHR. Methods MiRNA-9 expression was assessed by means of quantitative RT-PCR. Putative miR-9 targets were determined in silico and confirmed in luciferase reporter assays. miR-9 function was inhibited with sequence-specific antagomirs. The efficacy of DEX was assessed by quantifying glucocorticoid receptor (GR) cellular localization, protein phosphatase 2A (PP2A) activity, and AHR. Results Exposure of pulmonary macrophages to IFN-¿/LPS synergistically induced miR-9 expression; reduced levels of its target transcript, protein phosphatase 2 regulatory subunit B (B56) d isoform; attenuated PP2A activity; and inhibited DEX-induced GR nuclear translocation. Inhibition of miR-9 increased both PP2A activity and GR nuclear translocation in macrophages and restored steroid sensitivity in multiple models of steroid-resistant AHR. Pharmacologic activation of PP2A restored DEX efficacy and inhibited AHR. MiR-9 expression was increased in sputum of patients with neutrophilic but not those with eosinophilic asthma. Conclusion MiR-9 regulates GR signaling and steroid-resistant AHR. Targeting miR-9 function might be a novel approach for the treatment of steroid-resistant asthma.

DOI 10.1016/j.jaci.2014.11.044
Citations Scopus - 30Web of Science - 29
Co-authors Steven Maltby, Hock Tay, Joerg Mattes, Paul Foster
2015 Han S, Gao F, Yang W, Ren Y, Liang X, Xiong X, et al., 'Identification of an SCLC susceptibility rs7963551 genetic polymorphism in a previously GWAS-identified 12p13.33 RAD52 lung cancer risk locus in the Chinese population', International Journal of Clinical and Experimental Medicine, 8 16528-16535 (2015)

© 2015, E-Century Publishing Corporation. All rights reserved. As a well-known DNA repair gene, RAD52 plays an essential role in homologous recombination repair of double strand b... [more]

© 2015, E-Century Publishing Corporation. All rights reserved. As a well-known DNA repair gene, RAD52 plays an essential role in homologous recombination repair of double strand break, maintenance of genomic stability and prevention of cell malignant transformation. Previous genome-wide association studies (GWASs) have identified common genetic variants at 12p13.33 RAD52 locus associated with lung cancer risk in Caucasians. However, little or nothing has been known about the RAD52 single nucleotide polymorphisms (SNPs) in small cell lung cancer (SCLC) in the Chinese population. As a result, we examined the association between six RAD52 SNPs (rs10849605, rs1051669, rs10774474, rs11571378, rs7963551 and rs6489769) and SCLC susceptibility in Chinese. After 520 SCLC cases and 1040 controls in two independent case-control sets were genotyped, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. We found that only the RAD52 rs7963551 SNP was significantly associated with SCLC risk among six RAD52 SNPs genotyped. The odds of having the rs7963551 CA genotype in SCLC patients was 0.38 (95% CI = 0.24-0.62, P = 1.1×10-4) compared with the CC genotype. Stratified analyses of association between rs7963551 SNP and SCLC risk indicated that the functional polymorphism was only significantly associated with decreased risk among smokers but not nonsmokers. Our results demonstrated that the functional RAD52 rs7963551 SNP contributes to susceptibility to developing SCLC in the Chinese population.

Citations Scopus - 4
2015 Wang X, Ren Y, Wang Z, Xiong X, Han S, Pan W, et al., 'Down-regulation of 5S rRNA by miR-150 and miR-383 enhances c-Myc-rpL11 interaction and inhibits proliferation of esophageal squamous carcinoma cells', FEBS Letters, 589 3989-3997 (2015)

© 2015 Federation of European Biochemical Societies. 5S rRNA plays an important part in ribosome biology and is over-expression in multiple cancers. In this study, we found that 5... [more]

© 2015 Federation of European Biochemical Societies. 5S rRNA plays an important part in ribosome biology and is over-expression in multiple cancers. In this study, we found that 5S rRNA is a direct target of miR-150 and miR-383 in esophageal squamous cell carcinoma (ESCC). Overexpression of miR-150 and miR-383 inhibited ESCC cell proliferation in vitro and in vivo. Moreover, 5S rRNA silencing by miR-150 and miR-383 might intensify rpL11-c-Myc interaction, which attenuated role of c-Myc as an oncogenic transcriptional factor and dysregulation of multiple c-Myc target genes. Taken together, our results highlight the involvement of miRNAs in ribosomal regulation during tumorigenesis.

DOI 10.1016/j.febslet.2015.11.012
Citations Scopus - 12
2015 Wang X, Ren Y, Yang X, Xiong X, Han S, Ge Y, et al., 'MiR-190a inhibits epithelial-mesenchymal transition of hepatoma cells via targeting the long non-coding RNA treRNA', FEBS Letters, 589 4079-4087 (2015)

© 2015 Federation of European Biochemical Societies. treRNA is a long non-coding RNA (lncRNA) involved in cancer progression. In this study, we show that miR-190a can silence treR... [more]

© 2015 Federation of European Biochemical Societies. treRNA is a long non-coding RNA (lncRNA) involved in cancer progression. In this study, we show that miR-190a can silence treRNA post-transcriptionally. Suppression of treRNA by miR-190a led to significant changes of mesenchymal-epithelial transition markers and impaired migration and invasion capability of hepatoma cells. TCGA data indicated that miR-190a exhibited lower expression in hepatoma tissues, especially from patients with vascular tumor invasion, compared to normal tissues. Our results reveal the involvement of miR-190a-treRNA axis in hepatoma progression and shed light on lncRNA-based cancer therapies for hepatoma patients at high risk of metastasis.

DOI 10.1016/j.febslet.2015.11.024
Citations Scopus - 10
2015 Wang X, Li M, Wang Z, Han S, Tang X, Ge Y, et al., 'Silencing of long noncoding RNA MALAT1 by miR-101 and miR-217 inhibits proliferation, migration, and invasion of esophageal squamous cell carcinoma cells', Journal of Biological Chemistry, 290 3925-3935 (2015)

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Background: MALAT1, a highly conserved long non-coding RNA (lncRNA), acts as on... [more]

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Background: MALAT1, a highly conserved long non-coding RNA (lncRNA), acts as oncogene in multiple human cancers. Results: miR-101 and miR-217 can silenceMALAT1expression and then inhibit esophageal cancer proliferation, migration and invasion. Conclusion: Tumor suppressor miR-101 and miR-217 can negatively regulate MALAT1 expression. Significance: These data provide a new mechanism for MALAT1 regulation.

DOI 10.1074/jbc.M114.596866
Citations Scopus - 118
2015 Li B, Sun SZ, Yang M, Shi JL, Xu W, Wang XF, et al., 'The correlation between EGFR mutation status and the risk of brain metastasis in patients with lung adenocarcinoma', Journal of Neuro-Oncology, 124 79-85 (2015)

© 2015, Springer Science+Business Media New York. To explore the correlation between epidermal growth factor receptor (EGFR) mutation status and the risk of brain metastasis (BM) ... [more]

© 2015, Springer Science+Business Media New York. To explore the correlation between epidermal growth factor receptor (EGFR) mutation status and the risk of brain metastasis (BM) in patients with lung adenocarcinoma, the clinical data of 100 patients with pathologically confirmed lung adenocarcinoma and known EGFR mutation status at exon 18, 19, 20, or 21 were analyzed retrospectively. The incidence of BM was similar between patients with wild-type EGFR and those with EGFR mutations (p¿=¿0.48). However, among patients with EGFR mutations, the incidence of BM was significantly higher in patients with mutation at exon 19 than in patients with mutation at other sites (p¿=¿0.007). Besides, among patients with heterochronous BM, 66.7¿% had EGFR mutations. Regarding brain-metastasis-free survival (BMFS), patients with EGFR sensitive mutations (mutation at exon 19/21/and dual mutation) had significantly shorter BMFS compared with patients with wild-type EGFR (p¿=¿0.018). For patients treated only with chemotherapy, BM was an unfavorable prognostic factor. Patients with BM had worse overall survival compared with those without BM (p¿=¿0.035). However, in patients with BM and EGFR sensitive mutations, those treated with tyrosine kinase inhibitors (TKIs) had significantly longer overall survival compared with those treated with chemotherapy only (p¿=¿0.0081). In conclusion, among patients with EGFR mutations, those mutated at exon 19 had the highest incidence of BM. Furthermore, patients with EGFR mutations are more likely to develop heterochronous BM. The BMFS was significantly shorter in patients with EGFR sensitive mutations. TKIs improved the survival of patients with lung adenocarcinoma and BM who harbored EGFR sensitive mutations.

DOI 10.1007/s11060-015-1776-3
Citations Scopus - 11
2015 Li X, Wei J, Xu P, Yin X, Hu D, Zhang X, et al., 'The interaction of APEX1 variant with polycyclic aromatic hydrocarbons on increasing chromosome damage and lung cancer risk among male Chinese', Molecular Carcinogenesis, 54 E103-E111 (2015)

© 2014 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc. 54 S1 Matthew B. Schabath John DiGiovanni June 2015 10.1002/mc.22195 Article Articles © 2014 Wiley Periodicals, Inc..... [more]

© 2014 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc. 54 S1 Matthew B. Schabath John DiGiovanni June 2015 10.1002/mc.22195 Article Articles © 2014 Wiley Periodicals, Inc.. Polycyclic aromatic hydrocarbons (PAHs) are the most significant contributors to tobacco-induced lung carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central enzyme in the removal of apurinic/apyrimidinic sites caused by DNA damaging agents. This study aimed to investigate the potential interaction of APEX1 polymorphisms and PAHs on genetic damage and lung cancer risk among male Chinese. We recruited an occupational cohort of 922 male coke oven workers and determined their DNA damage levels by calculating the lymphocytic micronucleus (MN) frequencies. Two well-studied APEX1 polymorphisms (-307A>C and Asp148Glu) and their associations with MN frequencies were examined. The impact of MN-related single nucleotide polymorphism (SNP) on lung cancer risk was further investigated in two case-control studies including 1634 male lung cancer patients and 1678 controls. It was shown that, the APEX1 148Glu allele was associated with significantly higher MN frequencies than 148Asp allele, with strongest associations among the highest PAH-exposure workers (P=0.008). The APEX1 148Glu allele was also associated with increased lung cancer risk among male smokers, especially among heavy smokers in both case-control studies (odd ratio: 4.40, 95%CI: 3.29-5.72). In addition, APEX1 148Glu variant interacts with smoking in increasing male lung cancer risk, as measured by the attributable proportion due to interaction, which was 0.23 (95%CI: 0.06-0.39). This study showed evidence on interaction between APEX1 148Glu variant and cigarette smoking in increasing lung cancer susceptibility among male Chinese, which may be due to the synergistic effects of APEX1 148Glu and PAHs in increasing chromosome damage levels. The results provide a new insight into gene-interactions in lung carcinogenesis.

DOI 10.1002/mc.22195
Citations Scopus - 3
2015 Li Z, Guo Y, Zhou L, Ge Y, Wei L, Li L, et al., 'Association of a functional RAD52 genetic variant locating in a miRNA binding site with risk of HBV-related hepatocellular carcinoma', Molecular Carcinogenesis, 54 853-858 (2015)

© 2014 Wiley Periodicals, Inc.. As an important member in homologous recombination repair, RAD52 plays a crucial part in maintaining genomic stability and prevent carcinogenesis. ... [more]

© 2014 Wiley Periodicals, Inc.. As an important member in homologous recombination repair, RAD52 plays a crucial part in maintaining genomic stability and prevent carcinogenesis. Several cancer susceptibility RAD52 single nucleotide polymorphisms (SNPs) have been identified previously. However, little or nothing has been known about the RAD52 SNPs and their functional significance in hepatitis B viruses (HBV)-related hepatocellular carcinoma (HCC). Therefore, we investigated the association between five RAD52 SNPs (rs1051669, rs10774474, rs11571378, rs7963551, and rs6489769) and HBV-related HCC risk as well as its biological function in vivo. Genotypes were determined in two independent case-control sets from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The allele-specific regulation on RAD52 expression by the functional genetic variant was examined with normal liver tissues. We found that only the RAD52 rs7963551 SNP was significantly associated with HCC risk, with the odds of having the rs7963551 CC genotype in patients was 0.59 (95% CI=0.45-0.78, P=1.5×10<sup>-4</sup>, HCC cases versus chronic HBV carriers) or 0.65 (95% CI=0.52-0.81, P=1.1×10<sup>-4</sup>, HCC cases versus healthy controls) compared with the AA genotype. In the genotype-phenotype correlation analyses of 44 human liver tissue samples, rs7963551 CC or AC was associated with a statistically significant increase of RAD52 mRNA expression, which are consistent to functional relevance of allelic regulation of RAD52 expression by rs7963551 SNP and miRNA let-7 in cancer cells. Our data demonstrated that RAD52 functional rs7963551 SNP contributes to susceptibility to developing HCC.

DOI 10.1002/mc.22156
Citations Scopus - 18
2015 Ge Y, Yan X, Jin Y, Yang X, Yu X, Zhou L, et al., 'fMiRNA-192 and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma', PLoS Genetics, 11 (2015)

© 2015 Ge et al. Accumulated evidence demonstrated that long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis. However, it is still largely unknown how these lncRNAs... [more]

© 2015 Ge et al. Accumulated evidence demonstrated that long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis. However, it is still largely unknown how these lncRNAs were regulated by small ncRNAs, such as microRNAs (miRNAs), at the post-transcriptional level. We here use lncRNA HOTTIP as an example to study how miRNAs impact lncRNAs expression and its biological significance in hepatocellular carcinoma (HCC). LncRNA HOTTIP is a vital oncogene in HCC, one of the deadliest cancers worldwide. In the current study, we identified miR-192 and miR-204 as two microRNAs (miRNAs) suppressing HOTTIP expression via the Argonaute 2 (AGO2)-mediated RNA interference (RNAi) pathway in HCC. Interaction between miR-192 or miR-204 and HOTTIP were further confirmed using dual luciferase reporter gene assays. Consistent with this notion, a significant negative correlation between these miRNAs and HOTTIP exists in HCC tissue specimens. Interestingly, the dysregulation of the three ncRNAs was associated with overall survival of HCC patients. In addition, the posttranscriptional silencing of HOTTIP by miR-192, miR-204 or HOTTIP siRNAs could significantly suppress viability of HCC cells. On the contrary, antagonizing endogenous miR-192 or miR-204 led to increased HOTTIP expression and stimulated cell proliferation. In vivo mouse xenograft model also support the tumor suppressor role of both miRNAs. Besides the known targets (multiple 5¿ end HOX A genes, i.e. HOXA13), glutaminase (GLS1) was identified as a potential downstream target of the miR-192/-204-HOTTIP axis in HCC. Considering glutaminolysis as a crucial hallmark of cancer cells and significantly inhibited cell viability after silencingGLS1, we speculate that the miR-192/-204-HOTTIP axis may interrupt HCC glutaminolysis through GLS1 inhibition. These results elucidate that the miR-192/-204-HOTTIP axis might be an important molecular pathway during hepatic cell tumorigenesis. Our data in clinical HCC samples highlight miR-192, miR-204 and HOTTIP with prognostic and potentially therapeutic implications.

DOI 10.1371/journal.pgen.1005726
Citations Scopus - 51
2015 Tay HL, Kaiko GE, Plank M, Li JJ, Maltby S, Essilfie AT, et al., 'Antagonism of miR-328 Increases the Antimicrobial Function of Macrophages and Neutrophils and Rapid Clearance of Non-typeable Haemophilus Influenzae (NTHi) from Infected Lung', PLoS Pathogens, 11 (2015) [C1]

© 2015 Tay et al. Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to ... [more]

© 2015 Tay et al. Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.

DOI 10.1371/journal.ppat.1004549
Citations Scopus - 25Web of Science - 29
Co-authors Philip Hansbro, Joerg Mattes, Gerard Kaiko, Paul Foster, Steven Maltby, Hock Tay
2015 Xie R, Shi J, Qu Y, Tang P, Wu X, Yang M, Yuan Q, 'Synthesis and anti-tumor activities of novel phenyl substituted suberoylanilide hydroxamic acid derivatives against human cancer cells', Medicinal Chemistry, 11 636-648 (2015)

© 2015 Bentham Science Publishers. A facile and atom-economical boric acid catalyzed direct amidation without any coupling agents for the preparation of Suberoylanilide Hydroxamic... [more]

© 2015 Bentham Science Publishers. A facile and atom-economical boric acid catalyzed direct amidation without any coupling agents for the preparation of Suberoylanilide Hydroxamic Acid (SAHA) and SAHA-based inhibitors targeting anti-proliferation of cancer cells is described. It is applicable to the preparation of SAHAbased inhibitors having an unprotected hydroxyl group in the phenyl ring without the need of the protection. The in-vitro assays data indicate that the nature and the position of the substituents (activating and/or deactivating) in the capping group (phenyl ring) of SAHA-based inhibitors synthesized in this study have a vital impact on the potency of anti-proliferative activity against cancer cells. With low toxicity toward the normal cells, a number of synthesized SAHA-based inhibitors with two substituents in the phenyl ring possess higher antiproliferative activity than SAHA and Cisplatin toward six studied cancer cell lines: A375 human skin cancer cells, A549 human lung cancer cells, MGC80-3 human gastric cancer cells, H460 human lung cancer cells, H1299 human lung cancer cells, and HepG2 human liver cancer cells. Cisplatin is a common chemotherapeutic drug with high cytotoxicity for a variety of cancer treatments. The inhibitors provided in this study might signify future therapeutic drugs for cancer treatment.

DOI 10.2174/1573406411666150429154107
Citations Scopus - 6
2015 Xu X, Wang J, Zhu SM, Yang M, Fang Y, Zhao A, et al., 'Impact of alcohol dehydrogenase gene 4 polymorphisms on Esophageal squamous cell carcinoma risk in a Chinese population', PLoS ONE, 10 (2015)

© 2015 Xu et al. Background: Esophageal squamous cell carcinoma (ESCC) is very common in China and is also one of the most common cancers worldwide. The purpose of this study was ... [more]

© 2015 Xu et al. Background: Esophageal squamous cell carcinoma (ESCC) is very common in China and is also one of the most common cancers worldwide. The purpose of this study was to examine the associations between genetic variants of various cancer-related genes and the risk of ESCC. Methods: In this study, we first examined the association between 18 potentially disruptive genetic variants of 17 genes, including alcohol dehydrogenase 4 (ADH4) and checkpoint kinase 2(CHEK2), and ESCC risk in a Hangzhou population of 617 patients matched with 534 controls. Among the 18 single nucleotide polymorphisms (SNPs), two were validated in a Jinan population of 540 patients matched with 550 controls. Results: Sixteen SNPs in 15 genes, including CHEK2, did not have significantly different allele frequency distributions between ESCC patients and control subjects. A significantly increased risk of developing ESCC was revealed in subjects with the AA genotype of rs3805322 (ADH4) compared with those with the AG or GG genotype by unconditional univariate logistic regression analysis. Using a dominant model, the CC genotype of rs4822983 (CHEK2) had a marginally significant protective effect compared to the CT and TT genotypes. The association of ESCC risk with these two SNPs (rs3805322 and rs4822983) was further validated in a Jinan case-control set. Individuals with the ADH4 rs3805322 AA or AG genotype had ORs of 1.10 (95% CI = 0.81-1.49, P < 0.001) or 1.86 (95% CI = 1.33-2.59, P = 0.559), respectively, for developing ESCC compared with individuals with the GG genotype. CHEK2 rs4822983 CC carriers showed a marginally significantly decreased ESCC risk compared with those carrying the CT and TT genotypes in the validation set (95% CI = 0.61-1.01, P = 0.064). However, no evidence of interaction existed between the two SNPs and smoking or drinking in the Jinan case-control set. Conclusions: In conclusion, this current study provides substantial evidence that genetic polymorphisms of rs3805322 in the ADH4 gene may be associated with an increased risk of developing ESCC in two Chinese Han populations. Future studies to address the biological function of this polymorphism in the development of ESCC are warranted.

DOI 10.1371/journal.pone.0127304
Citations Scopus - 2
2015 Gao F, Xiong X, Pan W, Yang X, Zhou C, Yuan Q, et al., 'A regulatory MDM4 genetic variant locating in the binding sequence of multiple MicroRNAs contributes to susceptibility of small cell lung cancer', PLoS ONE, 10 (2015)

© 2015 Gao et al. A functional rs4245739 A&gt;C single nucleotide polymorphism (SNP) locating in the MDM43&apos;-untranslated (3&apos;-UTR) region creates a miR-191-5p or miR-887-... [more]

© 2015 Gao et al. A functional rs4245739 A>C single nucleotide polymorphism (SNP) locating in the MDM43'-untranslated (3'-UTR) region creates a miR-191-5p or miR-887-3p targeting sites. This change results in decreased expression of oncogene MDM4. Therefore, we examined the association between this SNP and small cell lung cancer (SCLC) risk as well as its regulatory function in SCLC cells. Genotypes were determined in two independent case-control sets consisted of 520SCLC cases and 1040 controls from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The impact of the rs4245739 SNP on miR-191-5p/miR-887-3p mediated MDM4 expression regulation was investigated using luciferase reporter gene assays. We found that the MDM4 rs4245739AC and CC genotypes were significantly associated with decreased SCLC susceptibility compared with the AA genotype in both case-control sets (Shandong set: OR=0.53, 95% CI=0.32-0.89, P=0.014; Jiangsu set: OR=0.47, 95% CI=0.26-0.879, P=0.017). Stratified analyses indicated that there was a significantly multiplicative interaction between rs4245739 and smoking (P<inf>interactioin</inf>=0.048). After co-tranfection of miRNAs and different allelic-MDM4 reporter constructs into SCLC cells, we found that the both miR-191-5p and miR-887-3p can lead to significantly decreased MDM4 expression activities in the construct with C-allelic 3'-UTR but not A-allelic 3'-UTR, suggesting a consistent genotypephenotype correlation. Our data illuminate that the MDM4rs4245739SNP contributes to SCLC risk and support the notion that gene 3'-UTR genetic variants, impacting miRNAbinding, might modify SCLC susceptibility. Copyright:

DOI 10.1371/journal.pone.0135647
Citations Scopus - 10
2015 Tian C, Chen Z, Ma X, Yang M, Wang Z, Dong Y, et al., 'Comparison of genetic variants in cancer-related genes between Chinese Hui and Han Populations', PLoS ONE, 10 (2015)

© 2015 Tian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reprod... [more]

© 2015 Tian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background The Chinese Hui population, as the second largest minority ethnic group in China, may have a different genetic background from Han people because of its unique demographic history. In this study, we aimed to identify genetic differences between Han and Hui Chinese from the Ningxia region of China by comparing eighteen single nucleotide polymorphisms in cancer-related genes. Methods DNA samples were collected from 99 Hui and 145 Han people from the Ningxia Hui Autonomous Region in China, and SNPs were detected using an improved multiplex ligase detection reaction method. Genotyping data from six 1000 Genomes Project population samples (99 Utah residents with northern and western European ancestry (CEU), 107 Toscani in Italy (TSI), 108 Yoruba in Ibadan (YRI), 61 of African ancestry in the southwestern US (ASW), 103 Han Chinese in Beijing (CHB), and 104 Japanese in Tokyo (JPT)) were also included in this study. Differences in the distribution of alleles among the populations were assessed using x2tests, and FST was used to measure the degree of population differentiation. Results We found that the genetic diversity of many SNPs in cancer-related genes in the Hui Chinese in Ningxia was different from that in the Han Chinese in Ningxia. For example, the allele frequencies of four SNPs (rs13361707, rs2274223, rs465498, and rs753955) showed different genetic distributions (p<0.05) between Chinese Ningxia Han and Chinese Ningxia Hui. Five SNPs (rs730506, rs13361707, rs2274223, rs465498 and rs753955) had different FST values (FST>0.000) between the Hui and Han populations. Conclusions These results suggest that some SNPs associated with cancer-related genes vary among different Chinese ethnic groups.We suggest that population differences should be carefully considered in evaluating cancer risk and prognosis as well as the efficacy of cancer therapy.

DOI 10.1371/journal.pone.0145170
Citations Scopus - 1
2015 Pan W, Yang J, Wei J, Chen H, Ge Y, Zhang J, et al., 'Functional BCL-2 regulatory genetic variants contribute to susceptibility of esophageal squamous cell carcinoma', Scientific Reports, 5 (2015)

B-cell lymphoma-2 (BCL-2) prevents apoptosis and its overexpression could promote cancer cell survival. Multiple functional BCL-2 genetic polymorphisms, such as rs2279115, rs18010... [more]

B-cell lymphoma-2 (BCL-2) prevents apoptosis and its overexpression could promote cancer cell survival. Multiple functional BCL-2 genetic polymorphisms, such as rs2279115, rs1801018 and rs1564483, have been identified previously and might be involved in cancer development through deregulating BCL-2 expression. Therefore, we examined associations between these three polymorphisms and esophageal squamous cell carcinoma (ESCC) susceptibility as well as its biological function in vivo. Genotypes were determined in two independent case-control sets consisted of 1588 ESCC patients and 1600 controls from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. The impact of the rs2279115 polymorphism on BCL-2 expression was detected using esophagus tissues. Our results demonstrated that the BCL-2 rs2279115 AA genotype was significantly associated with decreased ESCC risk compared with the CC genotype (OR = 0.72, 95% CI = 0.57-0.90, P = 0.005), especially in nonsmokers (OR = 0.42, 95% CI = 0.29-0.59, P = 0.001) or nondrinkers (OR = 0.44, 95% CI = 0.32-0.62, P = 0.002). Genotype-phenotype correlation studies demonstrated that subjects with the rs2279115 CA and AA genotypes had a statistically significant decrease of BCL-2 mRNA expression compared to the CC genotype in both normal and cancerous esophagus tissues. Our results indicate that the BCL-2 rs2279115 polymorphism contributes to ESCC susceptibility in Chinese populations.

DOI 10.1038/srep11833
Citations Scopus - 5
2014 Yang M, Eyers F, Xiang Y, Guo M, Young IG, Rosenberg HF, Foster PS, 'Expression profiling of differentiating eosinophils in bone marrow cultures predicts functional links between microRNAs and their target mRNAs', PLoS ONE, 9 (2014) [C1]

Background: MicroRNAs (miRNAs) are small non-coding RNAs that regulate complex transcriptional networks underpin immune responses. However, little is known about the specific miRN... [more]

Background: MicroRNAs (miRNAs) are small non-coding RNAs that regulate complex transcriptional networks underpin immune responses. However, little is known about the specific miRNA networks that control differentiation of specific leukocyte subsets. In this study, we profiled miRNA expression during differentiation of eosinophils from bone marrow (BM) progenitors (bmEos), and correlated expression with potential mRNA targets involved in crucial regulatory functions. Profiling was performed on whole BM cultures to document the dynamic changes in miRNA expression in the BM microenvironment over the differentiation period. miRNA for network analysis were identified in BM cultures enriched in differentiating eosinophils, and chosen for their potential ability to target mRNA of factors that are known to play critical roles in eosinophil differentiation pathways or cell identify. Methodology/Principal Findings: We identified 68 miRNAs with expression patterns that were up- or down- regulated 5-fold or more during bmEos differentiation. By employing TargetScan and MeSH databases, we identified 348 transcripts involved in 30 canonical pathways as potentially regulated by these miRNAs. Furthermore, by applying miRanda and Ingenuity Pathways Analysis (IPA), we identified 13 specific miRNAs that are temporally associated with the expression of IL-5Ra and CCR3 and 14 miRNAs associated with the transcription factors GATA-1/2, PU.1 and C/EBPe. We have also identified 17 miRNAs that may regulate the expression of TLRs 4 and 13 during eosinophil differentiation, although we could identify no miRNAs targeting the prominent secretory effector, eosinophil major basic protein. Conclusions/Significance: This is the first study to map changes in miRNA expression in whole BM cultures during the differentiation of eosinophils, and to predict functional links between miRNAs and their target mRNAs for the regulation of eosinophilopoiesis. Our findings provide an important resource that will promote the platform for further understanding of the role of these non-coding RNAs in the regulation of eosinophil differentiation and function. © 2014 Yang et al.

DOI 10.1371/journal.pone.0097537
Citations Scopus - 13Web of Science - 11
Co-authors Paul Foster
2014 Xiang Y, Eyers F, Young IG, Rosenberg HF, Foster PS, Yang M, 'Identification of MicroRNAs regulating the developmental pathways of bone marrow derived mast cells', PLoS ONE, 9 (2014) [C1]

Background: MicroRNAs (miRNAs) play important roles in leukocyte differentiation, although those utilised for specific programs and key functions remain incompletely characterised... [more]

Background: MicroRNAs (miRNAs) play important roles in leukocyte differentiation, although those utilised for specific programs and key functions remain incompletely characterised. As a global approach to gain insights into the potential regulatory role of miRNA in mast cell differentiation we characterised expression in BM cultures from the initiation of differentiation. In cultures enriched in differentiating mast cells we characterised miRNA expression and identified miRNA targeting the mRNA of putative factors involved in differentiation pathways and cellular identity. Detailed pathway analysis identified a unique miRNA network that is intimately linked to the mast cell differentiation program. Methodology/Principal Findings: We identified 86 unique miRNAs with expression patterns that were up- or down-regulated at 5-fold or more during bone marrow derived mast cells (BMMC) development. By employing TargetScan and MeSH databases, we identified 524 transcripts involved in 30 canonical pathways as potentially regulated by these specific 86 miRNAs. Furthermore, by applying miRanda and IPA analyses, we predict that 7 specific miRNAs of this group are directly associated with the expression of c-Kit and FceRIa and likewise, that 18 miRNAs promote expression of Mitf, GATA1 and c/EBPa three core transcription factors that direct mast cell differentiation. Furthermore, we have identified 11 miRNAs that may regulate the expression of STATs-3, -5a/b, GATA2 and GATA3 during differentiation, along with 13 miRNAs that target transcripts encoding Ndst2, mMCP4 and mMCP6 and thus may regulate biosynthesis of mast cell secretory mediators. Conclusions/ Significance: This investigation characterises changes in miRNA expression in whole BM cultures during the differentiation of mast cells and predicts functional links between miRNAs and their target mRNAs for the regulation of development. This information provides an important resource for further investigations of the contributions of miRNAs to mast cell differentiation and function. © 2014 Xiang et al.

DOI 10.1371/journal.pone.0098139
Citations Scopus - 14Web of Science - 12
Co-authors Paul Foster
2014 Li J, Yang M, Li P, Su Z, Gao P, Zhang J, 'Idiopathic pulmonary fibrosis will increase the risk of lung cancer', CHINESE MEDICAL JOURNAL, 127 3142-3149 (2014) [C1]
DOI 10.3760/cma.j.issn.0366-6999.20141346
Citations Scopus - 12Web of Science - 13
2014 Shan M, Yang X, Ezzati M, Chaturvedi N, Coady E, Hughes A, et al., 'A feasibility study of the association of exposure to biomass smoke with vascular function, inflammation, and cellular aging', Environmental Research, 135 165-172 (2014)

© 2014 Elsevier Inc. Background: Biomass smoke at higher concentrations is associated with respiratory symptoms and, after years of exposure, increased risk of respiratory disorde... [more]

© 2014 Elsevier Inc. Background: Biomass smoke at higher concentrations is associated with respiratory symptoms and, after years of exposure, increased risk of respiratory disorders in adults, but its effects on cardiovascular diseases are not well characterized, particularly compared with other pollution sources like tobacco smoke or traffic. Methods: We conducted a cross-sectional study and enrolled 25 women living in rural Sichuan, China. We measured integrated 24-h personal exposure to fine particulate matter (PM2.5) and black carbon, and measured PM2.5and black carbon in their kitchens. We assessed participants' brachial and central blood pressure and arterial stiffness using pulse wave analysis, and analyzed dried blood spot and buccal cell samples for C-reactive protein and relative telomere length. We also evaluated the difference in these physiological and biomarker measures between individuals with high (=median) versus low (<median) PM2.5exposure using multivariate regression. Results: Geometric mean 24-h PM2.5and black carbon exposures were 61µg/m3(95% CI: 48, 78) and 3.2µg/m3(95% CI: 2.3, 4.5), respectively. Average kitchen PM2.5and black carbon concentrations were only moderately correlated with personal exposures (PM2.5: r=0.41; black carbon: r=0.63), although they had similar means. Women in the high and low exposure groups were similar in age, obesity, socioeconomic status, salt intake, and physical activity. Women in the high PM2.5exposure group had higher mean brachial systolic blood pressure (SBP; difference=4.6mmHg, 95% CI -7.8, 16.9), central SBP (difference=3.1mmHg, 95% CI: -8.4, 14.5), central pulse pressure (difference=4.1mmHg; 95% CI: -4.2, 12.4), and augmentation index (difference=2.8%, 95% CI: -1.6, 7.2). High exposed women had 43% shorter telomere length (95% CI: -113, 28) than that of women in the low exposure group. There were no differences in pulse wave velocity or C-reactive protein between the two exposure groups. None of the results was statistically significant. Conclusions: Our results suggest that it is feasible to measure markers of vascular function and biomarkers of inflammation and oxidative stress in field studies of biomass smoke. Although many of the associations were in the expected direction, larger studies would be needed to establish the effects.

DOI 10.1016/j.envres.2014.09.006
Citations Scopus - 26
2014 Zhang X, Zhou L, Fu G, Sun F, Shi J, Wei J, et al., 'The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNA HOTAIR via a novel intronic enhancer', Carcinogenesis, 35 2062-2067 (2014)

Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), which could induce genome-wide retargeting of polycomb- repressive complex 2, trimethylates histone H3 lysine-27... [more]

Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), which could induce genome-wide retargeting of polycomb- repressive complex 2, trimethylates histone H3 lysine-27 (H3K27me3) and deregulation of multiple downstream genes, is involved in development and progression of esophageal squamous cell carcinoma (ESCC). We hypothesized that the functional single nucleotide polymorphisms (SNP) in HOTAIR may affect HOTAIR expression and/or its function and, thus, ESCC risk. Therefore, we examined the association between three haplotypetagging SNPs (htSNP) across the whole HOTAIR locus and ESCC risk as well as the functional relevance of an ESCC susceptibility SNP rs920778. Genotypes were determined in three independent case-control sets consisted of 2098 ESCC patients and 2150 controls. The allele-specific regulation on HOTAIR expression by the rs920778 SNP was investigated in vitro and in vivo. We found that the HOTAIR rs920778 TT carriers had a 1.37-fold, 1.78-fold and 2.08-fold increased ESCC risk in Jinan, Shijiazhuang and Huaian populations, respectively, compared with the CC carriers (P = 0.003, 7.7 × 10-4and 5.9 × 10-4). During inspecting functional relevance of the rs920778 SNP, we identified a novel intronic HOTAIR enhancer locating between +1719bp and +2353bp from the transcriptional start site through reporter assays. Moreover, there is an allelic regulation of rs920778 on HOTAIR expression via this enhancer in both ESCC cell lines and normal esophageal tissue specimens, with higher HOTAIR expression among T allele carriers. These results demonstrate that functional genetic variants influencing lncRNA regulation may explain a fraction of ESCC genetic basis. © The Author 2014. Published by Oxford University Press. All rights reserved.

DOI 10.1093/carcin/bgu103
Citations Scopus - 84
2014 Chen YD, Lu C, Wei J, Han S, Wang H, Jiang T, et al., '1p34.2 rs621559 and 14q21 rs398652 leukocyte telomere length-related genetic variants contribute to glioma susceptibility', Journal of Neuro-Oncology, 119 71-78 (2014)

Recent genome-wide association studies have identified several leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Our previous data demonstrated that ... [more]

Recent genome-wide association studies have identified several leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Our previous data demonstrated that two SNPs (rs398652 on 14q21 and rs621559 on 1p34.2) were associated with LTL and risk of esophageal squamous cell carcinoma in Chinese. However, the role of these genetic variants on glioma risk is still unknown. Therefore, we examined if these genetic variants have impact on the genetic susceptibility of glioma in Chinese. On the basis of analyzing 404 glioma patients and frequency-matched 820 controls, we found that subjects having the 1p34.2 rs621559 AG or GG genotype had an OR of 1.82 (95 % CI = 1.07-3.09, P = 0.026) or 2.12 (95 % CI = 1.26-3.56, P = 0.005) for developing glioma, respectively, compared with subjects having the rs621559 AA genotype. Similarly, the 14q21 rs398652 AG or GG genotype was associated with increased glioma risk (OR = 1.39, 95 % CI = 1.07-1.80, P = 0.012; OR = 1.52, 95 % CI = 1.04-2.20, P = 0.029) compared to AA genotype. In all, our results highlight the possible role of telomere in carcinogenesis. © 2014 Springer Science+Business Media.

DOI 10.1007/s11060-014-1466-6
Citations Scopus - 1
2014 Lu C, Chen YD, Han S, Wei J, Ge Y, Pan W, et al., 'A RAD52 genetic variant located in a miRNA binding site is associated with glioma risk in Han Chinese', Journal of Neuro-Oncology, 120 11-17 (2014)

© 2014, Springer Science+Business Media New York. As a crucial homologous recombination repair gene, RAD52 participates in maintenance of genomic stability and prevention of tumor... [more]

© 2014, Springer Science+Business Media New York. As a crucial homologous recombination repair gene, RAD52 participates in maintenance of genomic stability and prevention of tumorigenesis. Although several cancer susceptibility RAD52 single nucleotide polymorphisms (SNPs) have been identified previously, little was known on how the RAD52 SNPs are involved in glioma development in Han Chinese. Therefore, we examined the association between five RAD52 SNPs (rs1051669, rs10774474, rs11571378, rs7963551 and rs6489769) and glioma risk using a case¿control design. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. We found that only the RAD52 rs7963551 SNP was significantly associated with glioma risk, with the odds of having the rs7963551 AC or CC genotype in patients was 0.49 (95 % CI 0.37¿0.65, P = 9.2 × 10-6) or 0.39 (95 % CI 0.18¿0.81, P = 0.012) compared with the AA genotype. These data are consistent with functional relevance of allelic regulation of RAD52 expression by the rs7963551 SNP and miRNA let-7 in cancer cells. Stratified analyses elucidated that statistically significant association between glioma and rs7963551 SNP only existed in either astrocytic tumors (P = 6.3 × 10-6) or oligoastrocytic tumors (P = 0.002). In conclusion, our results support the hypothesis that genetic variants influencing miRNA-mediated regulation of tumor suppressor genes or oncogenes may contribute glioma susceptibility.

DOI 10.1007/s11060-014-1527-x
Citations Scopus - 7
2014 Zhang J, Li B, Ding X, Sun M, Li H, Yang M, et al., 'Genetic variants in inducible nitric oxide synthase gene are associated with the risk of radiation-induced lung injury in lung cancer patients receiving definitive thoracic radiation', Radiotherapy and Oncology, 111 194-198 (2014)

Background and purpose Nitric oxide (NO), mainly synthesized by inducible nitric oxide synthase (NOS2) in pathological conditions, plays an important role in cytotoxicity, inflamm... [more]

Background and purpose Nitric oxide (NO), mainly synthesized by inducible nitric oxide synthase (NOS2) in pathological conditions, plays an important role in cytotoxicity, inflammation and fibrosis. Elevations in exhaled NO after thoracic radiation have been reported to predict radiation-induced lung injury (RILI). This study examined whether genetic variations in NOS2 gene is associated with the risk of RILI. Material and methods A cohort of 301 patients between 2009 and 2011 were genotyped for 21 single nucleotide polymorphisms (SNPs) in the NOS2 gene by the Sequenom MassArray system. Kaplan-Meier cumulative probability was used to assess RILI risk and Cox proportional hazards analyses were performed to evaluate the effect of NOS2 genotypes on RILI. Results Multivariate analysis found that three SNPs (rs2297518, rs1137933 and rs16949) in NOS2 were significantly associated with risk of RILI = 2 (P value = 0.001, 0.000092, 0.001, respectively) after adjusting for other covariates. Their associations were independent of radiation dose and mean lung dose. Further haplotype analysis indicated that the ATC haplotype of three SNPs is associated with reducing the risk of developing RILI. Conclusion Our results demonstrate that genetic variants of NOS2 may serve as a reliable predictor of RILI in lung cancer patients treated with thoracic radiation. © 2014 Elsevier Ireland Ltd. All rights reserved.

DOI 10.1016/j.radonc.2014.03.001
Citations Scopus - 7
2014 Lv Z, Liu W, Li D, Liu L, Wei J, Zhang J, et al., 'Association of functional FEN1 genetic variants and haplotypes and breast cancer risk', Gene, 538 42-45 (2014)

Aim: As a tumor suppressor, FEN1 plays an essential role in preventing tumorigenesis. Two functional germline variants (-69G. &gt;. A and 4150G. &gt;. T) in the FEN1 gene have bee... [more]

Aim: As a tumor suppressor, FEN1 plays an essential role in preventing tumorigenesis. Two functional germline variants (-69G. >. A and 4150G. >. T) in the FEN1 gene have been associated with DNA damage levels in coke-oven workers and multiple cancer risk in general populations. However, it is still unknown how these genetic variants are involved in breast cancer susceptibility. Methods: We investigated the association between these polymorphisms and breast cancer risk in two independent case-control sets consisted of a total of 1100 breast cancer cases and 1400 controls. The influence of these variations on FEN1 expression was also examined using breast normal tissues. Results: It was found that the FEN1-69GG genotypes were significantly correlated to increased risk for developing breast cancer compared with the -69AA genotype in both sets [Jinan set: odds ratios (OR)=1.41, 95% confidence interval (CI)=1.20-1.65, P=1.9×10-5; Huaian set: OR=1.51, 95% CI=1.22-1.86, P=1.7×10-4]. Similar results were observed for 4150G>T polymorphism. The genotype-phenotype correlation analyses demonstrated that the -69G or 4150G allele carriers had more than 2-fold decreased FEN1 expression in breast tissues compared with -69A or 4150T carriers, suggesting that lower FEN1 expression may lead to higher risk for malignant transformation of breast cells. Conclusion: Our findings highlight FEN1 as an important gene in human breast carcinogenesis and genetic variants in FEN1 confer susceptibility to breast cancer. © 2014 Elsevier B.V.

DOI 10.1016/j.gene.2014.01.025
Citations Scopus - 11
2014 Zhang L, Li QX, Wu HL, Lu X, Yang M, Yu SY, Yuan XL, 'SNPs in the transforming growth factor-ß pathway as predictors of outcome in advanced lung adenocarcinoma with EGFR mutations treated with gefitinib', Annals of Oncology, 25 1584-1590 (2014)

Background: The aim of this study was to evaluate whether genetic variations in the transforming growth factor-ß (TGF-ß) pathway influenced clinical outcome of advanced lung adeno... [more]

Background: The aim of this study was to evaluate whether genetic variations in the transforming growth factor-ß (TGF-ß) pathway influenced clinical outcome of advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations treated with gefitinib. Patients and methods: Two hundred six patients with advanced lung adenocarcinomas were enrolled in this study. EGFR mutation in these tumors was detected. Among them, 106 patients with EGFR mutation and 37 of 100 patients with wild type were treated with gefitinib. Genotype of 33 single-nucleotide polymorphisms (SNPs) from 13 genes involved in the TGF-ß signaling pathway was determined, and their association with survival time was analyzed. Univariate and multivariate analyses were carried out to assess the role of biological/clinical parameters in progression-free survival (PFS) and overall survival (OS) using Pearson's ¿2test, log-rank test, and Cox proportional hazards model. Results: Among SNPs analyzed, multivariate analysis showed the cytidylate and thymidine (CT) genotype of SMAD3: rs11632964 was associated with a longer OS and PFS when the entire cohort of 143 patients were included; the association was significant in the patients with EGFR mutant tumors (30.8 versus 17.5 months; log-rank P = 0.020; and 20.8 versus 9.4 months; log-rank P = 0.001), when compared with patients with wild-type EGFR tumors. In patients with mutant EGFR, the CT genotype of SMAD3: rs11071938 and the cytidylate and cytidylate genotype of SMAD3: rs6494633 were also found to be associated with better PFS. Dual luciferase reporter assays showed gefitinib-resistant PC9/G cells transfected with SMAD3: rs11632964T allelic reporter construct showed significantly lower luciferase activities compared with cells expression C allelic reporter construct. There was significantly decreased expression of SMAD3 and pi-SMAD3 in the PC-9/G cells compared with PC-9. Conclusions: Among the candidate genes involved in the TGF-ß pathway, the polymorphisms of SMAD3 appear to be highly predictive of outcome of patients with lung adenocarcinoma after gefitinib treatment, especially in those with EGFR mutations. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

DOI 10.1093/annonc/mdu172
Citations Scopus - 2
2014 Yao J, Liu L, Yang M, 'Interleukin-23 receptor genetic variants contribute to susceptibility of multiple cancers', Gene, 533 21-25 (2014)

Aim: Interleukin-23 (IL-23) and IL-23 receptor (IL23R) play an important role during the T-helper 17 (Th17) cell-mediated inflammatory process as well as pathogenesis of multiple ... [more]

Aim: Interleukin-23 (IL-23) and IL-23 receptor (IL23R) play an important role during the T-helper 17 (Th17) cell-mediated inflammatory process as well as pathogenesis of multiple cancers. Several IL-23R single nucleotide polymorphisms (SNPs), especially rs6682925, rs10889677 and rs1884444 polymorphisms, are considered to have significant impacts on susceptibility of multiple cancers. A number of case-control studies have explored the role these genetic polymorphisms in development of carcinogenesis, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically investigate the associations between the three genetic variants and multiple cancer risk. Methods: A total of ten studies are eligible (12,211 patients and 14,650 controls). Pooled odds ratios (ORs) and the 95% confidence interval (95% CI) were appropriately calculated using either fixed-effect model or random-effect model. Results: Significant associations between rs6682925 or rs10889677 polymorphism and cancer risk were found (OR. = 1.11, 95% CI. = 1.03-1.21, P= 0.007; or OR. = 0.85, 95% CI. = 0.71-0.92, P= 0.001). However, there was no such association between rs1884444 genotypes and cancer susceptibility (P>. 0.05). Conclusion: These findings reveal that the IL-23R rs6682925 and rs10889677 genetic variants play a more important part in pathogenesis of multiple cancers. © 2013 Elsevier B.V.

DOI 10.1016/j.gene.2013.09.054
Citations Scopus - 13
2014 Chen S, Yang M, Hong S, Lu C, 'Nonionic fluorosurfactant as an ideal candidate for one-step modification of gold nanorods', Nanoscale, 6 3197-3205 (2014)

In this work, a novel protocol was developed for size tuning and cetyltrimethylammonium bromide (CTAB) removal of gold nanorods using commercially available nonionic fluorosurfact... [more]

In this work, a novel protocol was developed for size tuning and cetyltrimethylammonium bromide (CTAB) removal of gold nanorods using commercially available nonionic fluorosurfactants (FSN), an excellent candidate for PEG and other modification reagents. The tunable gold nanorods can easily be obtained by stopping the ligand replacement reaction at different time intervals. The FSN-coated gold nanorods are stable in the presence of high salt concentrations and over a wide range of pH values. Additionally, the cellular uptake experiments demonstrate that the FSN-coated gold nanorods have superior features in comparison to the widely used PEG-coated gold nanorods, such as high uptake amount, tunable uptake and excellent stability. Our findings suggest that FSN ligands are an ideal candidate for modifying gold nanorods with tunable aspect ratios, excellent biocompatibility, nontoxicity, and high stability, enabling conjugation to biomolecules for specific targeting, uptake, and delivery. © The Royal Society of Chemistry.

DOI 10.1039/c3nr05546a
Citations Scopus - 4
2014 Chen K, Ma H, Li L, Zang R, Wang C, Song F, et al., 'Erratum: Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women (Nature Communications (2014) 5 ((4682))', Nature Communications, 5 (2014)
DOI 10.1038/ncomms6828
2014 Pan W, Cheng G, Xing H, Shi J, Lu C, Wei J, et al., 'Leukocyte telomere length-related rs621559 and rs398652 genetic variants influence risk of HBV-related hepatocellular carcinoma', PLoS ONE, 9 (2014)

© 2014 Pan et al. Recent genome-wide association studies (GWAS) have identified eleven leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Since LTL ha... [more]

© 2014 Pan et al. Recent genome-wide association studies (GWAS) have identified eleven leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Since LTL has been associated with risk of many malignancies, LTL-related SNPs may contribute to cancer susceptibility. To test this hypothesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we genotyped these eleven LTL-related SNPs in a case-control set including 1186 HBV-related HCC cases, 508 chronic HBV carriers and 1308 healthy controls at the discovery stage. The associations of HCC risk with these SNPs were further confirmed in an independent case-control set. We found that 1p34.2 rs621559 and 14q21 rs398652 were significantly associated with HBV-related HCC risk (both P<0.005 after Bonferroni corrections). There was no significant difference of either rs621559 or rs398652 genotypes between chronic HBV carriers and healthy controls, demonstrating that the association was not due to predisposition to HBV infection. In the pooled analyses (1806 HBV-related HCC cases and 1954 controls), we observed a decreased HCC risk, 0.72-times, associated with the 1p34.2 rs621559 AA genotype compared to the GG genotype (P = 1.6×10-6). Additionally, there was an increased HCC risk, 1.27-fold, associated with the rs398652 GG genotype (P = 3.3×10-6). A statistical joint effect between the rs621559 GG and rs398652 GG genotypes may exist in elevating risk of HBV-related HCC. We show, for the first time, that rs398652 and rs621559 might be marker genetic variants for risk of HBV-related HCC in the Chinese population. Copyright:

DOI 10.1371/journal.pone.0110863
Citations Scopus - 7
2014 Wang H, Tong L, Wei J, Pan W, Li L, Ge Y, et al., 'The ALDH7A1 genetic polymorphisms contribute to development of esophageal squamous cell carcinoma', Tumor Biology, 35 12665-12670 (2014)

© 2014, International Society of Oncology and BioMarkers (ISOBM). Although the entire etiology of esophageal squamous cell carcinoma (ESCC) is still unclear, alcohol drinking has ... [more]

© 2014, International Society of Oncology and BioMarkers (ISOBM). Although the entire etiology of esophageal squamous cell carcinoma (ESCC) is still unclear, alcohol drinking has been identified as a major environmental risk factor. The aldehyde dehydrogenase (ALDH) superfamily members are major enzymes involved in the alcohol-metabolizing pathways. Accumulating evidences demonstrated that ALDH7A1, one of ALDH superfamily members, degrades and detoxifies acetaldehyde generated by alcohol metabolism and have been associated with development and prognosis of multiple cancers. However, it is still unknown if ALDH7A1 single nucleotide polymorphisms (SNPs) contribute to ESCC susceptibility. In this study, we examined the association between sixteen ALDH7A1 SNPs and risk of developing ESCC. Genotypes were determined in 2,098 ESCC patients and 2,150 controls (three independent hospital-based case¿control sets from different regions of China). Odds ratios (ORs) and 95¿% confidence intervals (CIs) were estimated by logistic regression. Our data demonstrated that only the ALDH7A1 rs13182402 SNP confer susceptibility to ESCC (For AG genotype, OR = 0.75, 95¿% CI = 0.66¿0.91, P = 4.8 × 10-6; for GG genotype, OR = 0.59, 95¿% CI = 0.41¿0.88, P = 0.003). These results are consistent to the biological functions of ALDH7A1 during alcohol metabolism and carcinogenesis.

DOI 10.1007/s13277-014-2590-9
Citations Scopus - 6
2014 Chen K, Ma H, Li L, Zang R, Wang C, Song F, et al., 'Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women', Nature Communications, 5 (2014)

Ovarian cancer is the leading cause of death from gynaecological malignancies worldwide. Here we perform a three-stage genome-wide association study (GWAS) in Han Chinese women to... [more]

Ovarian cancer is the leading cause of death from gynaecological malignancies worldwide. Here we perform a three-stage genome-wide association study (GWAS) in Han Chinese women to identify risk genetic variants for epithelial ovarian cancer (EOC). We scan 900,015 single-nucleotide polymorphisms (SNPs) in 1,057 EOC cases and 1,191 controls in stage I, and replicate 41 SNPs (P meta <10 a ^'4) in 960 EOC cases and 1,799 controls (stage II), and an additional 492 EOC cases and 1,004 controls (stage III). Finally, we identify two EOC susceptibility loci at 9q22.33 (rs1413299 in COL15A1, P meta =1.88 × 10 a ^'8) and 10p11.21 (rs1192691 near ANKRD30A, P meta =2.62 × 10 a ^'8), and two consistently replicated loci at 12q14.2 (rs11175194 in SRGAP1, P meta =1.14 × 10 a ^'7) and 9q34.2 (rs633862 near ABO and SURF6, P meta =8.57 × 10 a ^'7) (P<0.05 in all three stages). These results may advance our understanding of genetic susceptibility to EOC. © 2014 Macmillan Publishers Limited. All rights reserved.

DOI 10.1038/ncomms5682
Citations Scopus - 25
2014 Wang J, Wei J, Xu X, Pan W, Ge Y, Zhou C, et al., 'Replication study of ESCC susceptibility genetic polymorphisms locating in the ADH1B-ADH1C-ADH7 cluster identified by GWAS', PLoS ONE, 9 (2014)

China was one of the countries with highest esophageal squamous cell carcinoma (ESCC) incidence and mortality worldwide. Alcohol drinking has been identified as a major environmen... [more]

China was one of the countries with highest esophageal squamous cell carcinoma (ESCC) incidence and mortality worldwide. Alcohol drinking has been identified as a major environmental risk-factor related to ESCC. The alcohol dehydrogenase (ADH) family are major enzymes involved in the alcohol-metabolizing pathways, including alcohol dehydrogenase 1B (ADH1B) and ADH1C. Interestingly, ADH1B and ADH1C genes locate tandemly with ADH7 in a genomic segment as a gene cluster, and are all polymorphic. Several ESCC susceptibility single nucleotide polymorphisms (SNPs) of the ADH1B-ADH1C-ADH7 cluster have been identified previously through a genome-wide association study (GWAS). In the study, we examined the association between five ADH1B-ADH1C-ADH7 cluster SNPs (rs1042026, rs17033, rs1614972, rs1789903 and rs17028973) and risk of developing ESCC. Genotypes were determined in two independent case-control sets from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. Our data demonstrated that these ADH1B-ADH1C-ADH7 cluster SNPs confer susceptibility to ESCC in these two case-control sets, which were consistent to results of the previous GWAS. © 2014 Wang et al.

DOI 10.1371/journal.pone.0094096
Citations Scopus - 11
2014 Fan C, Wei J, Yuan C, Wang X, Jiang C, Zhou C, Yang M, 'The functional TP53 rs1042522 and MDM4 rs4245739 genetic variants contribute to non-hodgkin lymphoma risk', PLoS ONE, 9 (2014)

© 2014 Fan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reprodu... [more]

© 2014 Fan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. As a heterogeneous kind of malignances, Non-Hodgkin lymphoma (NHL) is the most common hematologic cancer worldwide with the significantly increased morbidity in China. Accumulated evidences demonstrated that oncoprotein MDM4 plays a crucial role in the TP53 tumor suppressor signaling pathway. An rs4245739 A>C polymorphism locating in the MDM4 3'-untranslated region creates a miR-191 target site and results in allele-specific MDM4 expression. In this study, we examined the association between this polymorphism as well as the TP53 Arg72Pro (rs1042522 G>C) genetic variant and Non-Hodgkin Lymphoma (NHL) risk in a Chinese Han population. Genotypes were determined in 200 NHL cases and 400 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. We found significantly increased NHL risk among carriers of the TP53 72Pro allele compared with those with the 72Arg allele (P = 0.002 for the Pro/Pro genotype). We also observed a significantly decreased NHL risks among carriers of the MDM4 rs4245739 C allele compared with those with the A allele in Chinese (P = 0.014 for the AC genotype). Stratified analyses revealed the associations between these SNPs and NHL risk are especially noteworthy in young or male individuals. Additionally, the associations are much pronounced in NHL patients with B-cell lymphomas or grade 3 or 4 disease. Our results indicate that the TP53 Arg72Pro and the MDM4 rs4245739 polymorphisms contribute to NHL susceptibility and support the hypothesis that genetic variants in the TP53 pathway genes can act as important modifiers of NHL risk.

DOI 10.1371/journal.pone.0107047
Citations Scopus - 12
2013 Eftekhari P, Hajizadeh S, Reza Raoufy M, Reza Masjedi M, Yang M, Hansbro N, et al., 'Preventive effect of N-acetylcysteine in a mouse model of steroid resistant acute exacerbation of asthma', EXCLI Journal, 12 184-192 (2013) [C1]

Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acety... [more]

Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acetylcysteine (NAC) on the airway hyper-responsiveness (AHR) and the accumulation of inflammatory cells in the airways in an animal model of steroid resistant acute exacerbation of asthma. Systemically sensitized Balb/C mice were exposed to Ovalbumin aerosol on days 13, 14, 15 and 16, followed by intratracheal lipopolysaccharide (LPS) to induce acute exacerbation. NAC (intraperitoneal, 320 mg/kg 30 min before and 12 hours after each challenge) reduced hyperresponsiveness with/out dexamethasone. LPS application caused neutrophilia in bronchoalveolar lavage fluid (BALF) and eosinophil count was higher than respective control in BALF as well as neutrophils after dexamethasone treatment. NAC significantly decreased neutrophil and eosinophil count in BALF as well as inflammatory cytokines (IL-13 and IL-5).We concluded that addition of NAC to asthma therapy has beneficial preventive effects in an animal model of steroid resistant acute exacerbation of asthma.

Citations Scopus - 3Web of Science - 2
Co-authors Paul Foster, Nicole Hansbro
2013 Shi J, Sun F, Peng L, Li B, Liu L, Zhou C, et al., 'Leukocyte telomere length-related genetic variants in 1p34.2 and 14q21 loci contribute to the risk of esophageal squamous cell carcinoma', International Journal of Cancer, 132 2799-2807 (2013)

Short leukocyte telomere length has been associated with significantly increased risk of esophageal cancer. A previous genome-wide association study demonstrated that four SNPs (r... [more]

Short leukocyte telomere length has been associated with significantly increased risk of esophageal cancer. A previous genome-wide association study demonstrated that four SNPs (rs398652 on 14q21, rs621559 on 1p34.2, rs6028466 on 20q11.22 and rs654128 on 6q22.1) were associated with leukocyte telomere length in Caucasians. However, the role of these genetic variants on esophageal squamous cell carcinoma (ESCC) susceptibility is still unknown. Therefore, we investigated whether these polymorphisms have impact on leukocyte telomere length and the risk of ESCC in Chinese. After measuring leukocyte telomere length of 550 healthy individuals, we observed that both rs621559 and rs398652 genetic variants are significantly associated with leukocyte telomere length. On the basis of analyzing 1550 ESCC patients and frequency-matched 1620 controls from 4 medical centers in China, we found that 0.71-fold decreased risk of ESCC is associated with the rs621559 AA genotype compared with the rs621559 GG genotype (p = 5.9 × 10-6). We also detected a moderately increased OR for ESCC that was associated with the 14q21 rs398652 G allele (p = 6.5 × 10-4). It has been shown that both rs621559 and rs398652 polymorphisms were significantly associated with ESCC risk in additive, recessive or dominant genetic models. Stratified analyses demonstrated that these associations were more pronounced in males. Our results highlight the complexity of genetic regulation of telomere length and further support the important role of telomere in carcinogenesis. Copyright © 2012 UICC.

DOI 10.1002/ijc.27959
Citations Scopus - 18
2013 Zhang X, Wei J, Zhou L, Zhou C, Shi J, Yuan Q, et al., 'A functional BRCA1 coding sequence genetic variant contributes to risk of esophageal squamous cell carcinoma', Carcinogenesis, 34 2309-2313 (2013)

As a tumor suppressor, breast cancer susceptibility gene 1 (BRCA1) plays a pivotal role in maintaining genomic stability. A functional rs799917 T&gt;C polymorphism located in the ... [more]

As a tumor suppressor, breast cancer susceptibility gene 1 (BRCA1) plays a pivotal role in maintaining genomic stability. A functional rs799917 T>C polymorphism located in the BRCA1 coding sequence could influence miR-638-mediated regulation of BRCA1 expression. Therefore, we examined the association between this polymorphism and esophageal squamous cell carcinoma (ESCC) risk as well as its biological function. Genotypes were determined in two independent case-control studies consisted of 1128 ESCC patients and 1150 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The allele-specific regulation on BRCA1 expression by the polymorphism was investigated in vitro and in vivo. We found that the BRCA1 rs799917 CC genotype was significantly associated with increased ESCC risk compared with the TT genotype in both studies (Jinan population: OR = 1.28, 95% CI = 1.04-1.58, P = 0.020; Huaian population: OR = 1.46, 95% CI = 1.17-1.83, P = 0.001). Stratified analyses with pooled data indicated that a multiplicative interaction between rs799917 and smoking or drinking in intensifying ESCC risk was evident (gene-smoking: Pinteraction= 5.8 × 10-5; gene-drinking: Pinteraction= 7.1 × 10-7). In vitro experiments indicate that miR-638 could negatively regulate BRCA1 expression and enhance proliferation of ESCC cells. In vivo BRCA1 messenger RNA expression analyses showed that the rs799917 C allele carriers had significantly decreased BRCA1 expression in both normal and cancerous esophagus tissues compared with T allele carriers, suggesting that lower BRCA1 expression may lead to higher risk for malignant transformation of esophagus cells. These results suggest that BRCA1 functional rs799917 polymorphism is involved in susceptibility to developing ESCC, alone and in a gene-environment interaction manner. © The Author 2013.

DOI 10.1093/carcin/bgt213
Citations Scopus - 36
2013 Deng Q, Guo H, Dai J, Yang L, Wu C, Wang Q, et al., 'Imputation-based association analyses identify new lung cancer susceptibility variants in CDK6 and SH3RF1 and their interactions with smoking in Chinese populations', Carcinogenesis, 34 2010-2016 (2013)

Cell cycle regulation, apoptosis, oxidative stress and inflammation response play critical roles in the development of smokinginduced lung cancer. However, it is still not well kn... [more]

Cell cycle regulation, apoptosis, oxidative stress and inflammation response play critical roles in the development of smokinginduced lung cancer. However, it is still not well known whether their genetic variants are associated with lung cancer susceptibility. In this study, we performed imputation-based association analyses to investigate the influence of common genetic variants in these pathways and their interactions with smoking on lung cancer susceptibility. We first selected 24 042 unvalidated genetic variants in 798 genes from the imputed dataset of the previous lung cancer genome-wide association study in 2331 cases and 3077 controls, and then conducted additional two-stage validations in 4133 cases and 4522 controls. We found a genome-wide significant (P < 5.0 × 10-8) association for rs2282987 in CDK6 at 7q21.2 [odds ratio (OR) = 1.18, combined Padd = 2.27 × 10-9] and a consistent association for rs2706748 in SH3RF1 at 4q32.3 (OR = 1.17, combined Padd = 5.10 × 10-6). Interaction analyses showed that rs2282987 and rs2706748 interacted with both smoking status (Pinteraction were 1.04 × 10-2and 3.03 × 10-2, respectively) and smoking history (Pinteraction were 1.21 × 10-2and 5.21 × 10-2, respectively) to contribute to lung cancer susceptibility in subjects aged 51-60 years. These results further underscore the contribution of genetic variants involved in pathways of cell cycle regulation and apoptosis to lung cancer susceptibility, and highlight gene-environment interactions in lung cancer etiology, especially in subjects aged 51-60 years. © The Author 2013. Published by Oxford University Press. All rights reserved.

DOI 10.1093/carcin/bgt145
Citations Scopus - 3
2013 Chen YD, Zhang X, Qiu XG, Li J, Yuan Q, Jiang T, Yang M, 'Functional FEN1 genetic variants and haplotypes are associated with glioma risk', Journal of Neuro-Oncology, 111 145-151 (2013)

As a tumor suppressor, FEN1 plays an essential role in keeping genomic instability and preventing tumorigenesis. There are two functional genetic variants (-69G&gt;A and 4150G&gt;... [more]

As a tumor suppressor, FEN1 plays an essential role in keeping genomic instability and preventing tumorigenesis. There are two functional genetic variants (-69G>A and 4150G>T) in the FEN1 gene, which have been associated with DNA damage levels in coke-oven workers as well as risks of lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer in general populations. However, it is still unknown how these polymorphisms and their haplotypes are associated with glioma risk. Therefore, we investigated the role of these polymorphisms in glioma development using a case-control design in a Chinese population. The impact of the haplotypes constructed by these two polymorphisms on glioma risk was also examined. It was observed that the FEN1-69GG or 4150GG genotype were significantly associated to increased glioma risk compared with the -69AA or 4150TT genotype [Odds ratios (OR) = 1.87, 95 % confidence interval (CI) = 1.23-2.85, P = 0.003; or OR = 1.87, 95 % CI = 1.23-2.84, P = 0.003). The associations were more pronounced among female subjects (For -69AG or GG genotype: OR = 2.35, 95 % CI = 1.22-4.52; for 4150TG or GG genotype: OR = 2.33, 95 % CI = 1.21-4.48) and patients with grade 1 or 2 disease (For -69AG or GG genotype: OR = 2.21, 95 % CI = 1.20-4.05; for 4150TG or GG genotype: OR = 2.45, 95 % CI = 1.31-4.58). Additionally, the G-69G4150haplotype was also significantly associated with increased glioma risk compared with the A-69T4150haplotype. Our results suggest that FEN1 polymorphisms and haplotypes are associated with glioma risk. © 2012 Springer Science+Business Media New York.

DOI 10.1007/s11060-012-1007-0
Citations Scopus - 19
2013 Liu J, Tang X, Li M, Lu C, Shi J, Zhou L, et al., 'Functional MDM4 rs4245739 genetic variant, alone and in combination with P53 Arg72Pro polymorphism, contributes to breast cancer susceptibility', Breast Cancer Research and Treatment, 140 151-157 (2013)

The oncoprotein MDM4 plays an essential role in P53 tumor suppressor pathway through negative regulation of P53 function. It has been reported that the rs4245739 A &gt; C polymorp... [more]

The oncoprotein MDM4 plays an essential role in P53 tumor suppressor pathway through negative regulation of P53 function. It has been reported that the rs4245739 A > C polymorphism located in the MDM4 3'-untranslated region creates a miR-191 target site and results in decreased MDM4 expression. Therefore, we investigated the association of the MDM4 rs4245739 polymorphism as well as the P53 Arg72Pro genetic variant with the breast cancer risk. Genotypes were determined in two independent case-control sets consisting of 1100 breast cancer cases and 1400 controls from two regions of China. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. Our results demonstrated that the MDM4 rs4245739 AC and CC genotypes were significantly associated with decreased breast cancer risk compared to the AA genotype in both the case-control sets (Jinan set: OR = 0.55, 95 % CI 0.40-0.76, P = 2.3 × 10-4; Huaian set: OR = 0.41, 95 % CI 0.25-0.67, P = 3.1 × 10-4). The P53 Arg/Pro genotype or Pro/Pro genotype was significantly associated with an increased risk of developing breast cancer, compared to the P53 Arg/Arg genotype in both the case-control sets (all P < 0.05). Interestingly, we observed a combinational effect between MDM4 rs4245739 and P53 Arg72Pro variants in attenuating breast cancer risk, highlighting the importance of the P53 tumor suppressor pathway genes during malignant transformation. Our results also support the hypothesis that genetic variants interrupting miRNA-mediated gene regulation might be important genetic modifiers of breast cancer risk. © 2013 Springer Science+Business Media New York.

DOI 10.1007/s10549-013-2615-x
Citations Scopus - 27
2013 Nguyen HCN, Xie W, Yang M, Hsieh CL, Drouin S, Lee GSM, Kantoff PW, 'Expression differences of circulating microRNAs in metastatic castration resistant prostate cancer and low-risk, localized prostate cancer', Prostate, 73 346-354 (2013)

BACKGROUND Recent studies show that microRNAs (miRNAs), small non-coding RNAs that negatively regulate gene expression, may have potential for monitoring cancer status. We investi... [more]

BACKGROUND Recent studies show that microRNAs (miRNAs), small non-coding RNAs that negatively regulate gene expression, may have potential for monitoring cancer status. We investigated circulating miRNAs in prostate cancer that may be associated with the progression of hormone-sensitive primary tumors to metastatic castration resistant prostate cancer (CRPC) after androgen deprivation therapy. METHODS Using genome-wide expression profiling by TaqMan Human MicroRNA Arrays (Applied Biosystems) and/or quantitative real-time polymerase chain reaction, we compared the expression levels of miRNAs in serum samples from 28 patients of low-risk localized disease, 30 of high-risk localized disease and 26 of metastatic CRPC. RESULTS We demonstrated that serum samples from patients of low risk, localized prostate cancer and metastatic CRPC patients exhibit distinct circulating miRNA signatures. MiR-375, miR-378, and miR-141 were significantly over-expressed in serum from CRPC patients compared with serum from low-risk localized patients, while miR-409-3p was significantly under-expressed. In prostate primary tumor samples, miR-375 and miR-141 also had significantly higher expression levels compared with those in normal prostate tissue. CONCLUSIONS Circulating miRNAs, particularly miR-375, miR-141, miR-378, and miR-409-3p, are differentially expressed in serum samples from prostate cancer patients. In the search for improved minimally invasive methods to follow cancer pathogenesis, the correlation of disease status with the expression patterns of circulating miRNAs may indicate the potential importance of circulating miRNAs as prognostic markers for prostate cancer progression. Prostate 73: 346-354, 2013. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

DOI 10.1002/pros.22572
Citations Scopus - 111
2013 Chen YD, Feng J, Fang T, Yang M, Qiu XG, Jiang T, 'Effect of intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy on clinical outcomes in patients with glioblastoma multiforme', Chinese Medical Journal, 126 2320-2324 (2013)

Background Few studies were reported on the comparison of clinical outcomes between intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) i... [more]

Background Few studies were reported on the comparison of clinical outcomes between intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in the treatment of glioblastoma multiforme (GBM). This study aimed to determine whether IMRT improves clinical outcomes compared with 3D-CRT in patients with GBM. Methods The records of 54 patients with newly-diagnosed GBM from July 2009 to December 2010 were reviewed. The patients underwent postoperative IMRT or 3D-CRT with concurrent and adjuvant temozolomide. Kaplan-Meier method and log rank test were used to estimate differences of patients' survival. Results The median follow-up was 13 months. Of the 54 patients, fifty (92.6%) completed the combined modality treatment. The 1-year overall survival rate (OS) was 79.6%. The pattern of failure was predominantly local. A comparative analysis revealed that no statistical difference was observed between the IMRT group (n=21) and the 3D-CRT group (n=33) for 1-year OS (89.6% vs. 75.8%, P=0.795), or 1-year progression-free survival (PFS) (61.0% vs. 45.5%, P=0.867). In dosimetric comparison, IMRT seemed to allow better sparing of organs at risk than 3D-CRT did (P=0.050, P=0.055). However, there was no significant difference for toxicities of irradiation between the IMRT group and the 3D-CRT group. Conclusions Our preliminary results suggested that delivering standard radiation doses by IMRT is unlikely to improve local control or overall survival for GBM compared with 3D-CRT. Given this lack of survival benefit and increased costs ofIMRT, the utilization ofIMRTtreatment for GBM needs to be carefully rationalized.

DOI 10.3760/cma.j.issn.0366-6999.20130218
Citations Scopus - 6
2013 Zhang L, Yuan X, Chen Y, Du XJ, Yu S, Yang M, 'Role of EGFR SNPs in survival of advanced lung adenocarcinoma patients treated with Gefitinib', Gene, 517 60-64 (2013)

Aim: As a novel molecularly targeting agent for non-small-cell lung cancer (NSCLC), Gefitinib can block its tyrosine kinase activity of the epidermal growth factor receptor (EGFR)... [more]

Aim: As a novel molecularly targeting agent for non-small-cell lung cancer (NSCLC), Gefitinib can block its tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Genetic variations in EGFR may affect its protein function or expression and lead to diverse outcomes in NSCLC patients after Gefitinib therapy. Therefore, this prospective study examined whether EGFR single nucleotide polymorphisms (SNPs) are associated with different survival time in advanced lung adenocarcinoma patients treated with Gefitinib. Methods: One hundred and twenty-eight patients with stage IIIB or IV lung adenocarcinoma receiving Gefitinib target therapy between 2008 and 2010 were recruited in this study. Six EGFR haplotype-tagging SNPs were genotyped by the Sequenom MassArray system. Survival by different genotypes was compared using Kaplan-Meier methods. Cox proportional hazards models were applied to estimate the effect of prognostic factors on overall survival (OS) and progression-free survival (PFS). Results: After the median 16.6. months of follow-up, the unfavorable EGFR rs2293347AA or GA genotype was significantly correlated with shorter OS (AA vs. GG: 2.0 vs. 21.0. months; hazard ratio (HR) = 2.44, 95% confidence interval (CI) = 1.06-5.56; P= 0.036; GA vs. GG: 15.0 vs. 21.0. months; HR = 1.75, 95%CI = 1.08-2.86, P= 0.025) compared with the favorable rs2293347GG genotype. The prognostic significance of EGFR rs4947492 polymorphism on OS also existed (GG carriers vs. AA carriers: median OS = 24.6 vs. 14.9. months, HR = 0.29, 95%CI = 0.10-0.83, P= 0.021). No significant associations were found among other EGFR SNPs and survival. Conclusion: EGFR rs2293347 and rs4947492 SNPs might be potential predictive markers of OS in advanced lung adenocarcinoma patients treated with Gefitinib. © 2012 Elsevier B.V.

DOI 10.1016/j.gene.2012.12.087
Citations Scopus - 12
2013 Liu L, Wu G, Xue F, Li Y, Shi J, Han J, et al., 'Functional CYP1A1 genetic variants, alone and in combination with smoking, contribute to development of head and neck cancers', European Journal of Cancer, 49 2143-2151 (2013)

CYP1A1 plays an essential role in pathogenesis of head and neck cancers. Functional CYP1A1 Ile462Val and MspI single nucleotide polymorphisms (SNP) are considered to have signific... [more]

CYP1A1 plays an essential role in pathogenesis of head and neck cancers. Functional CYP1A1 Ile462Val and MspI single nucleotide polymorphisms (SNP) are considered to have significant effects on risk of head and neck cancers. Several case-control studies have examined how these genetic polymorphisms are involved in development of this group of malignancies, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically examine the associations between these functional genetic variants and head and neck cancer risk. A total of 28 studies are eligible for CYP1A1 Ile462Val SNP (4639 patients and 4701 controls), and 22 studies for MspI SNP (4168 patients and 4638 controls). Pooled odds ratios (ORs) and the 95% confidence interval (95% CI) were appropriately calculated using either fixed-effect model or random-effect model. There was no association between Ile462Val polymorphism and head and neck cancer risk (OR = 1.23, 95% CI = 0.99-1.53, P = 0.062). However, in a stratified analysis, a statistically significant correlation between this SNP and pharyngeal cancer risk was observed (OR = 1.76, 95% CI = 1.32-2.33, P < 0.001). For MspI SNP, our data indicated that carriers of TC and CC genotypes had a 34% increased risk to develop head and neck cancers compared to TT carriers (95% CI = 1.15-1.57, P < 0.001). This effect was even more pronounced in smokers (OR = 2.98, 95% CI = 1.69-5.26, P < 0.001), demonstrating that gene-smoking interaction intensifying carcinogenesis may exist. These findings reveal that the functional CYP1A1 MspI genetic variant, alone and in combination with smoking, plays a more important role in pathogenesis of head and neck cancers.© 2013 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.ejca.2013.01.028
Citations Scopus - 13
2013 Beckett EL, Stevens RL, Jarnicki AG, Kim RY, Hanish I, Hansbro NG, et al., 'A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis', The Journal of Allergy and Clinical Immunology, 131 752-762 (2013) [C1]
Citations Scopus - 93Web of Science - 96
Co-authors Emma Beckett, Nicole Hansbro, Philip Hansbro, Jay Horvat, Simon Keely, Paul Foster, Peter Wark
2013 Foster PS, Plank MW, Collison AM, Tay HL, Kaiko GE, Li J, et al., 'The emerging role of microRNAs in regulating immune and inflammatory responses in the lung', Immunological Reviews, 253 198-215 (2013) [C1]
Citations Scopus - 54Web of Science - 54
Co-authors Philip Hansbro, Hock Tay, Paul Foster, Adam Collison, Gerard Kaiko, Joerg Mattes
2013 Zhou L, Zhang X, Li Z, Zhou C, Li M, Tang X, et al., 'Association of a Genetic Variation in a miR-191 Binding Site in MDM4 with Risk of Esophageal Squamous Cell Carcinoma', PLoS ONE, 8 (2013)

As an oncoprotein, MDM4 plays a key part in P53 tumor suppressor pathway through negatively regulating P53 function. It has been reported that an rs4245739 A&gt;C polymorphism loc... [more]

As an oncoprotein, MDM4 plays a key part in P53 tumor suppressor pathway through negatively regulating P53 function. It has been reported that an rs4245739 A>C polymorphism locating in the MDM4 3'-untranslated region creates a miR-191 target site and results in decreased MDM4 expression. Therefore, we investigated the association between this polymorphism and esophageal squamous cell carcinoma (ESCC) risk as well as its biological function in vivo. Genotypes were determined in two independent case-control sets consisted of 1128 ESCC cases and 1150 controls from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The impact of the polymorphism on MDM4 expression was examined with esophagus tissues. Our results demonstrated that the MDM4 rs4245739 AC and CC genotypes were significantly associated with decreased ESCC risk compared with the AA genotype in both case-control sets (Jinan set: OR = 0.54, 95% CI = 0.35-0.82, P = 0.004; Huaian set: OR = 0.68, 95% CI = 0.45-0.99, P = 0.049). Stratified analyses revealed that a multiplicative interaction between rs4245739 and smoking or drinking was evident (Gene-smoking: Pinteractioin= 0.022; gene-drinking: Pinteractioin= 0.032). After detecting In vivo MDM4 mRNA expression, we found that the rs4245739 AC and CC genotype carriers had significantly decreased MDM4 expression in normal esophagus tissues compared with AA genotype carriers, indicating a consistent genotype-phenotype correlation. Our results elucidate that the MDM4 rs4245739 polymorphism contributes to susceptibility of ESCC and support the hypothesis that genetic variants, interrupting miRNA-mediated gene regulation, may modify cancer risk. © 2013 Zhou et al.

DOI 10.1371/journal.pone.0064331
Citations Scopus - 41
2013 Hansbro PM, Scott GV, Essilfie A-T, Kim RY, Starkey MR, Nguyen D, et al., 'Th2 cytokine antagonists: Potential treatments for severe asthma', Expert Opinion on Investigational Drugs, 22 49-69 (2013) [C1]
Citations Scopus - 37Web of Science - 37
Co-authors Gerard Kaiko, Jay Horvat, Malcolm Starkey, Philip Hansbro, Paul Foster
2013 Li JJ, Tay HL, Plank M, Essilfie A-T, Hansbro PM, Foster PS, Yang M, 'Activation of Olfactory Receptors on Mouse Pulmonary Macrophages Promotes Monocyte Chemotactic Protein-1 Production', PLOS ONE, 8 (2013) [C1]
DOI 10.1371/journal.pone.0080148
Citations Scopus - 12Web of Science - 5
Co-authors Philip Hansbro, Paul Foster, Hock Tay
2012 Yang M, Sun T, Zhou Y, Wang L, Liu L, Zhang X, et al., 'The functional cytotoxic T lymphocyte-associated Protein 4 49G-To-A genetic variant and risk of pancreatic cancer', Cancer, 118 4681-4686 (2012)

BACKGROUND: Antitumor T lymphocytes play an essential part in immune surveillance of cancer cells. Cytotoxic T lymphocyte-associated Protein 4 (CTLA-4) is a negative regulator of ... [more]

BACKGROUND: Antitumor T lymphocytes play an essential part in immune surveillance of cancer cells. Cytotoxic T lymphocyte-associated Protein 4 (CTLA-4) is a negative regulator of T cell activation and proliferation and therefore influences immune surveillance of carcinogenesis of pancreas. Thus, this study examined the association between functional CTLA-4 49G-To-A (49G>A) single-nucleotide polymorphism and pancreatic cancer risk. METHODS: Genotypes were determined in 368 patients with pancreatic cancer and 926 controls, and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS: A significant increased risk of pancreatic cancer was found to be associated with the CTLA-4 49G>A single-nucleotide polymorphism. Compared with noncarriers, the OR of developing pancreatic cancer for CTLA-4 49 GA or AA carriers was 1.75 (95% CI = 1.34-2.30, P = 4.83 × 10-5) or 2.54 (95% CI = 1.67-3.87, P = 1.36 × 10-5), respectively. In stratified analyses, the association was more pronounced in GA and AA carriers aged =60 years (OR = 3.10, 95% CI = 2.15-4.47, Pinteraction=.002, smokers with GA and AA genotypes (OR = 3.92, 95% CI = 2.39-6.43, Pinteraction=.037), and drinkers with GA and AA genotypes (OR = 4.55, 95% CI = 2.65-7.82, Pinteraction=.042), compared with GG carriers. Moreover, a supermultiplicative interaction between the CTLA-4 49AA genotype and smoking plus drinking was also evident in intensifying risk of pancreatic cancer (Pinteraction= 5.64 times 10 bsupesup). CONCLUSIONS: These results suggest that CTLA-4 49G>A polymorphism is involved in susceptibility to developing pancreatic cancer, alone and in a gene-environment interaction manner. © 2012 American Cancer Society.

DOI 10.1002/cncr.27455
Citations Scopus - 27
2012 Liu L, Zhou C, Zhou L, Peng L, Li D, Zhang X, et al., 'Functional FEN1 genetic variants contribute to risk of hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer', Carcinogenesis, 33 119-123 (2012)

As a DNA repair protein, Flap endonuclease 1 (FEN1) plays crucial parts in preventing carcinogenesis. Two functional germ line variants (-69G &gt; A and 4150G &gt; T) in the FEN1 ... [more]

As a DNA repair protein, Flap endonuclease 1 (FEN1) plays crucial parts in preventing carcinogenesis. Two functional germ line variants (-69G > A and 4150G > T) in the FEN1 gene have been associated with DNA damage levels in coke oven workers and lung cancer risk in general populations. However, the role of these genetic variants on gastrointestinal cancer susceptibility is unknown. Therefore, we evaluated the association between these polymorphisms and gastrointestinal cancer risk in two independent case-control cohorts consisted of a total of 1850 gastrointestinal cancer (hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer) patients and 2222 healthy controls. The impact of these variations on FEN1 expression was also examined using liver, esophagus, stomach and colon normal tissues. It was found that the FEN1 -69GG genotypes were significantly correlated to increased risk for developing gastrointestinal cancer compared with the -69AA genotype in both cohorts [Jinan cohort: odds ratios (OR) = 2.14, 95% confidence interval (CI) = 1.47-2.80, P = 1.0 × 10-6; Huaian cohort: OR = 1.93, 95% CI = 1.37-2.50, P = 0.5 × 10-6]. Similar results were observed for 4150G > T polymorphism. In the combined meta-analyses, OR for -69GG or 4150GG genotype was 2.02 (95% CI = 1.59-2.45) or 1.86 (95% CI = 1.45-2.28) compared with -69AA or 4150TT genotype. In vivo FEN1 messenger RNA expression analyses showed that the -69G or 4150G allele carriers had ~2-fold decreased FEN1 expression in gastrointestinal tissues compared with -69A or 4150T carriers, indicating that lower FEN1 expression may lead to higher risk for malignant transformation of gastrointestinal cells. Our results highlight FEN1 as an important gene in human gastrointestinal oncogenesis and genetic polymorphisms in FEN1 confer susceptibility to gastrointestinal cancers. © The Author 2011. Published by Oxford University Press. All rights reserved.

DOI 10.1093/carcin/bgr250
Citations Scopus - 47
2012 Sun T, Yang M, Chen S, Balk S, Pomerantz M, Hsieh CL, et al., 'The altered expression of MiR-221/-222 and MiR-23b/-27b is associated with the development of human castration resistant prostate cancer', Prostate, 72 1093-1103 (2012)

BACKGROUND. We have previously identified seven miRs-miR-221, -222, -23b, -27b, -15a, -16-1, and -203, that are differentially expressed in the hormone sensitive LNCaP cell line a... [more]

BACKGROUND. We have previously identified seven miRs-miR-221, -222, -23b, -27b, -15a, -16-1, and -203, that are differentially expressed in the hormone sensitive LNCaP cell line and the hormone resistant LNCaP-abl cell line and hypothesized that these miRs may characterize certain subtypes of human castration resistant prostate cancer (CRPC). METHODS. Functional studies in cell culture systems have been performed to determine the effect of alternated expression level on cellular response to androgen treatment. To determine the clinical relevance of the expression patterns of these miRs, we compared the expression levels of these seven miRs in normal prostate tissues from 86 individuals, prostate tumor tissues from 34 individuals with localized hormone naïve disease, and bone-derived metastatic CRPC tissues from 17 individuals. RESULTS. The altered expression of miR-221/-222 (as previously described) or miR-203 affected the cellular response to androgen treatment, suggesting their potential involvement in the transition to CRPC. However, the expression of miR-23b, -27b, -15a, and -16-1 did not have a significant influence in the cellular response to androgen treatment, suggesting that these miRs may not play a causative role in the CRPC phenotype. Comparison of the expression levels of these miRs in tissue samples revealed that strikingly, ~90% of the analyzed metastatic CRPC tumors could be characterized by the increased miR-221/-222 expression and the down-regulated miR-23b/-27b expression. CONCLUSIONS. This finding suggests that altered miR-221/-222 and miR-23b/-27b expression may be associated with the CRPC process. © 2011 Wiley Periodicals, Inc.

DOI 10.1002/pros.22456
Citations Scopus - 45
2012 Zhou L, Yuan Q, Yang M, 'A functional germline variant in the P53 polyadenylation signal and risk of esophageal squamous cell carcinoma', Gene, 506 295-297 (2012)

Aim: P53 plays a critical role in the maintenance of genomic stability as well as the control of cell growth and apoptosis. Recently, an uncommon . P53 genetic variant (rs78378222... [more]

Aim: P53 plays a critical role in the maintenance of genomic stability as well as the control of cell growth and apoptosis. Recently, an uncommon . P53 genetic variant (rs78378222) was reported to be significantly associated with multiple cancers in Caucasians in a genome-wide association study. rs78378222 locates in the 3'-untranslated region of the . P53 gene, and this A-to-C polymorphism results in changes of the AATAAA polyadenylation signal to AATACA, which leads to impaired 3'-end processing of . P53 mRNA and decreased . P53 expression. Methods: We evaluated the association between this polymorphism and esophageal squamous cell carcinoma (ESCC) risk in a case-control cohort consisting of 405 ESCC patients and 810 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Results: We did observe this polymorphism with low minor allele frequency in Chinese Han population. Additionally, significantly increased ESCC risk was associated with P53 rs78378222 A>C polymorphism. Compared with rs78378222AA carriers, the OR of developing ESCC for AC carriers was 3.22 (95% CI=1.71-6.33, P=1.34×10-4). Conclusion: These results suggest that this functional uncommon . P53 rs78378222 variant is associated with ESCC risk in the current Han Chinese population. © 2012 Elsevier B.V..

DOI 10.1016/j.gene.2012.07.007
Citations Scopus - 17
2012 Yu D, Shi J, Sun T, Du X, Liu L, Zhang X, et al., 'Pharmacogenetic role of ERCC1 genetic variants in treatment response of platinum-based chemotherapy among advanced non-small cell lung cancer patients.', Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 33 877-884 (2012)

The excision repair cross-complementation group 1 (ERCC1) plays an essential role in DNA repair and has been linked to resistance to platinum-based anticancer drugs among advanced... [more]

The excision repair cross-complementation group 1 (ERCC1) plays an essential role in DNA repair and has been linked to resistance to platinum-based anticancer drugs among advanced non-small cell lung cancer (NSCLC) patients. We systematically evaluate whether ERCC1 Asn118Asn and C8092A genetic variants are associated with treatment response of platinum chemotherapy. We preformed a meta-analysis using ten eligible cohort studies (including 11 datasets) with a total of 1,252 NSCLC patients to summarize the existing data on the association between the ERCC1 Asn118Asn and C8092A polymorphisms and response to platinum regiments. Odds ratio or hazard ratio with 95% confidence interval were calculated to estimate the correlation. We found that neither ERCC1 C8092A polymorphism nor Asn118Asn variant is associated with different response of platinum-based treatment among advanced NSCLC patients. Additionally, these two genetic variants are not related to treatment response in either Caucasian patients or Asian patients. Our meta-analysis indicates that the ERCC1 Asn118Asn and C8092A polymorphisms may not be good prognostic biomarkers for platinum-based chemotherapy in patients with stage III-IV NSCLC.

DOI 10.1007/s13277-011-0314-y
Citations Scopus - 20
2012 Yang M, Kumar RK, Hansbro PM, Foster PS, 'Emerging roles of pulmonary macrophages in driving the development of severe asthma', Journal of Leukocyte Biology, 91 557-569 (2012) [C1]
Citations Scopus - 54Web of Science - 56
Co-authors Philip Hansbro, Paul Foster
2012 Cai X, Yang M, 'The functional MDM2 T309G genetic variant but not P53 Arg72Pro polymorphism is associated with risk of sarcomas: A meta-analysis', Journal of Cancer Research and Clinical Oncology, 138 555-561 (2012)

Purpose: The P53-MDM2 pathway plays a central role in sarcoma pathogenesis. Functional P53 Arg72Pro and MDM2 T309G single-nucleotide polymorphisms (SNP) are considered to have sig... [more]

Purpose: The P53-MDM2 pathway plays a central role in sarcoma pathogenesis. Functional P53 Arg72Pro and MDM2 T309G single-nucleotide polymorphisms (SNP) are considered to have significant effects on risk of sarcomas. Methods: Several molecular epidemiology studies have evaluated how these genetic variants are involved in sarcoma development, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically examine the association between these functional SNPs and sarcoma risk. Results: There are four studies eligible for P53 Arg72Pro SNP (466 sarcoma patients and 552 controls), and three studies for MDM2 T309G SNP (355 sarcoma patients and 645 controls). Pooled odds ratios were appropriately calculated using either fixed-effect model or random-effect model. We did not find a significant association between P53 Arg72Pro polymorphism and sarcoma risk. However, in a stratified analysis, a statistically significant correlation between this SNP and osteosarcoma risk was observed. For MDM2 T309G variant, pooled results from the metaanalysis indicate that carriers of TG and GG genotypes showed a 34% increased risk to develop sarcomas compared to TT carriers. Conclusion: These results suggest that the functional MDM2 T309G genetic variant may play a more important role in carcinogenesis of sarcoma. © Springer-Verlag 2011.

DOI 10.1007/s00432-011-1124-8
Citations Scopus - 14
2012 Liu T, Yang M, Wang T, Yuan Q, 'Prediction strategy of adsorption equilibrium time based on equilibrium and kinetic results to isolate taxifolin', Industrial and Engineering Chemistry Research, 51 454-463 (2012)

We proposed a systematic strategy based on the studies about the adsorption performance of AB-8 macroporous adsorption resins for prediction of the equilibrium time in taxifolin i... [more]

We proposed a systematic strategy based on the studies about the adsorption performance of AB-8 macroporous adsorption resins for prediction of the equilibrium time in taxifolin isolation. Batch experiments were appropriately designed to obtain the best fitting model and to gain insight into the adsorption mechanisms. A modified Langmuir model was used to calculate the adsorption capacity at the adsorption equilibrium point (Qe). Subsequently, the reformed pseudo-second-order model was employed to predict the effects of the second-order rate index (k2Qe) on the adsorption time (t). Then, the effects of the initial adsorption factor (Ri) on the relative adsorption time (t/te) were predicted by the reformed intraparticle diffusion model. On the basis of mathematical deduction, the value of the adsorption equilibrium time (te) can be predicted, which may lead to reduced sampling in adsorption kinetics studies. Furthermore, the good agreement between experimental and predicted data confirmed the reliability of the proposed strategy. © 2011 American Chemical Society.

DOI 10.1021/ie201197r
Citations Scopus - 8
2012 Kumar RK, Yang M, Herbert C, Foster PS, 'Interferon-¿, pulmonary macrophages and airway responsiveness in asthma', Inflammation and Allergy - Drug Targets, 11 292-297 (2012) [C1]
Citations Scopus - 15
Co-authors Paul Foster
2011 Wang W, Hansbro PM, Foster PS, Yang M, 'An alternate STAT6-independent pathway promotes eosinophil influx into blood during allergic airway inflammation', PLoS ONE, 6 (2011) [C1]
DOI 10.1371/journal.pone.0017766
Citations Scopus - 9Web of Science - 7
Co-authors Philip Hansbro, Paul Foster
2011 Zhou C, Liu J, Li Y, Liu L, Zhang X, Ma CY, et al., 'MicroRNA-1274a, a modulator of sorafenib induced a disintegrin and metalloproteinase 9 (ADAM9) down-regulation in hepatocellular carcinoma', FEBS Letters, 585 1828-1834 (2011)

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with poor prognosis. Sorafenib, a multikinase inhibitor, has been widely used to treat patients with advanced H... [more]

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with poor prognosis. Sorafenib, a multikinase inhibitor, has been widely used to treat patients with advanced HCC in clinic. We postulated that microRNAs (miRNA) might be involved in HCC target-chemotherapy with sorafenib. MiRNA profile of HepG2 was evaluated after cells were treated with vehicle or sorafenib and alterations in miRNA expression occurred with 14 miRNAs. MiR-1274a, which is up-regulated by sorafenib, could significantly repress expression of ADAM9, a protease that is involved in sorafenib target-therapy of HCC, in HCC cells. Taken together, our data emphasizes a new miRNA-based mechanism of sorafenib antitumor therapy. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI 10.1016/j.febslet.2011.04.040
Citations Scopus - 36
2011 Wang L, Yang M, Fan X, Zhu X, Xu T, Yuan Q, 'An environmentally friendly and efficient method for xylitol bioconversion with high-temperature-steaming corncob hydrolysate by adapted Candida tropicalis', Process Biochemistry, 46 1619-1626 (2011)

This study reports a new process to prepare corncob hemicellulose hydrolysate through high temperature steaming (HTS) for xylitol bioconversion by adapted Candida tropicalis. Unde... [more]

This study reports a new process to prepare corncob hemicellulose hydrolysate through high temperature steaming (HTS) for xylitol bioconversion by adapted Candida tropicalis. Under the optimal corncob hydrolysis conditions of 160 °C and 120 min, the maximum xylose yield was more than 20%. The optimal fermentative parameters from the HTS hydrolysate is as follows: initial xylose concentration of 140 g l-1, initial pH 6.0, initial cell concentration of 1.2 g l-1and 30 °C using a two-step dissolved oxygen process with a rotary shaker speed at 200 rpm for the first 24-26 h and then at 150 rpm until 48 h of fermentation. The highest xylitol yield (71.4%) and volumetric productivity (2.12 g l-1h-1) were obtained from the HTS hydrolysate, which were 158% and 149%, respectively, higher than the results obtained from the acid hydrolysate. Additionally, the amount of inhibitors produced by the HTS hydrolysis and the burden of ion exchange purification after fermentation with HTS hydrolysate were much lower compared with the acid hydrolysate. Therefore, fermentation with corncob HTS hydrolysate is an environmentally friendly and efficient method to produce xylitol, demonstrating a wide potential application in xylitol bioconversion. © 2011 Elsevier Ltd.

DOI 10.1016/j.procbio.2011.05.004
Citations Scopus - 30
2011 Yang M, Zhang L, Bi N, Ji W, Tan W, Zhao L, et al., 'Association of P53 and ATM polymorphisms with risk of radiation-induced pneumonitis in lung cancer patients treated with radiotherapy', International Journal of Radiation Oncology Biology Physics, 79 1402-1407 (2011)

Purpose: Radiation-induced pneumonitis (RP) is the most common dose-limiting complication in lung cancer patients treated with radiotherapy. Accumulating evidence indicates that P... [more]

Purpose: Radiation-induced pneumonitis (RP) is the most common dose-limiting complication in lung cancer patients treated with radiotherapy. Accumulating evidence indicates that P53 and the ataxia telangiectasia-mutated protein (ATM) - dependent signaling response cascade play a crucial role in radiation-induced diseases. Consistent with this, our previous study showed that a functional genetic ATM polymorphism was associated with increased RP risk. Methods and Materials: To evaluate the role of genetic P53 polymorphism in RP, we analyzed the P53 Arg72Pro polymorphism in a cohort including 253 lung cancer patients receiving thoracic irradiation. Results: We found that the P53 72Arg/Arg genotype was associated with increased RP risk compared with the 72Pro/Pro genotype. Furthermore, the P53 Arg72Pro and ATM -111G>A polymorphisms display an additive combination effect in intensifying the risk of developing RP. The cross-validation test showed that 63.2% of RP cases can be identified by P53 and ATM genotypes. Conclusions: These results indicate that genetic polymorphisms in the ATM-P53 pathway influence susceptibility to RP and genotyping P53 and ATM polymorphisms might help to identify patients susceptible to developing RP when receiving radiotherapy. © 2011 Elsevier Inc.

DOI 10.1016/j.ijrobp.2009.12.042
Citations Scopus - 31
2011 Yang M, Xie W, Mostaghel E, Nakabayashi M, Werner L, Sun T, et al., 'SLCO2B1 and SLCO1B3 may determine time to progression for patients receiving androgen deprivation therapy for prostate cancer', Journal of Clinical Oncology, 29 2565-2573 (2011)

Purpose: Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of... [more]

Purpose: Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT. Patients and Methods: A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays. Results: Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (Pinteraction= .041). Conclusion: Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer. © 2011 by American Society of Clinical Oncology.

DOI 10.1200/JCO.2010.31.2405
Citations Scopus - 79
2011 Knappskog S, Bjørnslett M, Myklebust LM, Huijts PEA, Vreeswijk MP, Edvardsen H, et al., 'The MDM2 Promoter SNP285C/309G Haplotype Diminishes Sp1 Transcription Factor Binding and Reduces Risk for Breast and Ovarian Cancer in Caucasians', Cancer Cell, 19 273-282 (2011)

MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T &gt; G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis ... [more]

MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%-7.8%) of healthy individuals carry the SNP285C/309G haplotype. In vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n = 1993) and breast (n = 1973) cancer patients versus healthy controls (n = 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58-0.94) and breast cancer (OR 0.79; CI 0.62-1.00) among SNP309G carriers. © 2011 Elsevier Inc.

DOI 10.1016/j.ccr.2010.12.019
Citations Scopus - 64
2011 Zhou L, Zhang X, Chen X, Liu L, Lu C, Tang X, et al., 'GC Glu416Asp and Thr420Lys polymorphisms contribute to gastrointestinal cancer susceptibility in a Chinese population', International Journal of Clinical and Experimental Medicine, 5 72-79 (2011)

Vitamin D has potent anticancer properties, especially against gastrointestinal cancers. Group-specific component (GC), a key member of vitamin D pathway proteins, could bind to a... [more]

Vitamin D has potent anticancer properties, especially against gastrointestinal cancers. Group-specific component (GC), a key member of vitamin D pathway proteins, could bind to and transport vitamin D to target organs. As a polymorphic protein, two common coding single nucleotide polymorphisms (SNP) [Glu416Asp (rs7041) and Thr420Lys (rs4588)] were identified in its gene. These SNPs have been associated to circulating vitamin D levels and several cancer risks in different populations. However, there is no report on their role in gastrointestinal cancer development among Chinese to date. Therefore, we examined the association between these variants and risk of gastrointestinal cancers in a case-control cohort including 964 patients with four gastrointestinal cancers (hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer) and 1187 controls. Odds ratios and 95% confidence intervals were estimated by logistic regression. We found that GC Thr420Lys polymorphism has significant impact on the risk of developing gastrointestinal cancers, especially colorectal cancer. Additionally, subjects who carrying GC Asp416-Lys420haplotype, which contains the at-risk 420Lys allele, also showed significantly increased risk to develop gastrointestinal cancers. In conclusion, our study demonstrated that common genetic variants and haplotypes in GC may influence individual susceptibility to gastrointestinal cancers in Chinese population.

Citations Scopus - 19
2010 Guo Y, Zhang X, Yang M, Miao X, Shi Y, Yao J, et al., 'Functional evaluation of missense variations in the human MAD1L1 and MAD2L1 genes and their impact on susceptibility to lung cancer', Journal of Medical Genetics, 47 616-622 (2010)

Background: Human MAD1 mitotic arrest deficient-like 1 (MAD1L1) and MAD2 mitotic arrest deficient-like 1 (MAD2L1) are two interactive proteins playing important roles in maintaini... [more]

Background: Human MAD1 mitotic arrest deficient-like 1 (MAD1L1) and MAD2 mitotic arrest deficient-like 1 (MAD2L1) are two interactive proteins playing important roles in maintaining spindle checkpoint function. This study examined the functional relevance of missense coding single nucleotide polymorphisms (SNPs) in MAD1L1 and MAD2L1 and their association with susceptibility to lung cancer. Methods: SNPs in the MAD2L1 coding region were discovered by sequencing and impact of MAD1L1 and MAD2L1 variants on spindle checkpoint function was examined by flow cytometry and mitotic index assay. The associations of MAD1L1 and MAD2L1 variants with lung cancer were analysed in a case-control cohort of 1000 patients and 1000 controls. ORs and 95% CIs were estimated by logistic regression. Results: A novel C-to-A SNP at codon 84 of MAD2L1 (Leu84Met substitution) was discovered. Cells expressing MAD2L1-84Met and MAD1L1-558His had impaired spindle checkpoint function, with a lower 4N-DNA content and mitotic index when treated with nocodazole. Case-control analysis showed that the MAD2L1 Leu84Met SNP was associated with increased risk of lung cancer in an allele dose dependent manner, with the ORs being 2.55 (95% CI 1.95 to 3.33) for the Leu/Met and 2.68 (95% CI 2.05 to 3.48) for the Met/Met genotype compared with the Leu/Leu genotype. The MAD1L1 558 His/His genotype was also associated with 1.4-fold elevated lung cancer risk compared with the Arg/Arg genotype. Conclusion: These results suggest that genetic variants in MAD1L1 and MAD2L1 confer susceptibility to lung cancer, which might result from reduced spindle checkpoint function due to attenuated function of MAD1L1 and/or MAD2L1.

DOI 10.1136/jmg.2009.074252
Citations Scopus - 19
2010 Zhang L, Yang M, Bi N, Fang M, Sun T, Ji W, et al., 'ATM polymorphisms are associated with risk of radiation-induced pneumonitis', International Journal of Radiation Oncology Biology Physics, 77 1360-1368 (2010)

Purpose: Since the ataxia telangiectasia mutated (ATM) protein plays crucial roles in repair of double-stranded DNA breaks, control of cell cycle checkpoints, and radiosensitivity... [more]

Purpose: Since the ataxia telangiectasia mutated (ATM) protein plays crucial roles in repair of double-stranded DNA breaks, control of cell cycle checkpoints, and radiosensitivity, we hypothesized that variations in this gene might be associated with radiation-induced pneumonitis (RP). Methods and Materials: A total of 253 lung cancer patients receiving thoracic irradiation between 2004 and 2006 were included in this study. Common Terminology Criteria for Adverse Events version 3.0 was used to grade RP. Five haplotype-tagging single nucleotide polymorphisms (SNPs) in the ATM gene were genotyped using DNA from blood lymphocytes. Hazard ratios (HRs) and 95% confidence intervals (CIs) of RP for genotypes were computed by the Cox model, adjusted for clinical factors. The function of the ATM SNP associated with RP was examined by biochemical assays. Results: During the median 22-month follow-up, 44 (17.4%) patients developed grade = 2 RP. In multivariate Cox regression models adjusted for other clinical predictors, we found two ATM variants were independently associated with increased RP risk. They were an 111G > A) polymorphism (HR, 2.49; 95% CI, 1.07-5.80) and an ATM 126713G > A polymorphism (HR, 2.47; 95% CI, 1.16-5.28). Furthermore, genotype-dependent differences in ATM expression were demonstrated both in cell lines (p < 0.001) and in individual lung tissue samples (p = 0.003), which supported the results of the association study. Conclusions: Genetic polymorphisms of ATM are significantly associated with RP risk. These variants might exert their effect through regulation of ATM expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy. Copyright © 2010 Elsevier Inc.

DOI 10.1016/j.ijrobp.2009.07.1675
Citations Scopus - 41
2010 Tai J, Yang M, Ni X, Yu D, Fang J, Tan W, et al., 'Genetic polymorphisms in cytochrome P450 genes are associated with an increased risk of squamous cell carcinoma of the larynx and hypopharynx in a Chinese population', Cancer Genetics and Cytogenetics, 196 76-82 (2010)

The purpose of this study was to examine whether functional polymorphisms in the cytochrome P450 (CYP) enzyme genes affect the risk of developing larynx and hypopharynx squamous c... [more]

The purpose of this study was to examine whether functional polymorphisms in the cytochrome P450 (CYP) enzyme genes affect the risk of developing larynx and hypopharynx squamous cell carcinoma (SCC). We investigated CYP1A1, CYP1B1, CYP2E1, and CYP3A4 polymorphisms in 278 patients with laryngeal and hypopharyngeal SCC and 278 control subjects by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Subjects with the CYP1A1 3798CC or TC genotype had an odds ratio (OR) of 3.26 (95% confidence interval CI = 1.76 - 6.03) or 1.56 (95% CI = 1.06 - 2.31), compared with those with the TT genotype. An increased risk was also associated with the CYP1A1 462Val/Val genotype (OR = 2.39, 95% CI = 1.11 - 5.16), compared with the TT genotype. Haplotype analysis suggested a synergistic effect of these two polymorphisms. A multiplicative joint effect between the CYP1A1 3798 T > C polymorphism and smoking was observed. The OR (95% CI) of the TC or CC genotype for nonsmokers and smokers of >20 pack-years were 1.85 (0.99 - 3.44) or 8.15 (4.35 - 15.26), respectively (Ptrend< 0.05). The CYP1A1 single-nucleotide polymorphisms are associated with an increased risk of developing smoking-related laryngeal and hypopharyngeal SCC in a Han Chinese population. © 2010.

DOI 10.1016/j.cancergencyto.2009.08.015
Citations Scopus - 29
2010 Zhang L, Yang M, Bi N, Ji W, Wu C, Tan W, et al., 'Association of TGF-ß1 and XPD polymorphisms with severe acute radiation-induced esophageal toxicity in locally advanced lung cancer patients treated with radiotherapy', Radiotherapy and Oncology, 97 19-25 (2010)

Purpose: Radiation-induced esophageal toxicity (RIET) is a dose-limiting toxicity in lung cancer patients receiving radiotherapy. Accumulating evidence indicates that DNA repair a... [more]

Purpose: Radiation-induced esophageal toxicity (RIET) is a dose-limiting toxicity in lung cancer patients receiving radiotherapy. Accumulating evidence indicates that DNA repair and the cytokine pathways play essential roles in radiation-induced diseases. Genetic polymorphisms of genes in these pathways may affect gene function and/or gene expression and lead to different treatment-related esophageal toxicity. Materials and methods: This study investigated the association of 21 polymorphisms in 14 genes, with the occurrence of =grade 2 acute RIET. Genotypes were analyzed among 213 stage III lung cancer patients receiving radiotherapy. Results: We used Cox proportional hazard model to examine the effects of genotypes on =grade 2 acute RIET risk and Kaplan-Meier estimator to compare effects of different genotypes on such risk. Multivariate analysis showed that CT or TT genotype of TGF-ß1-509C/T polymorphism was associated with a significantly higher RIET risk (adjusted hazard ratio [HR] = 2.47; 95% confidence interval (CI) = 1.17-5.24; P = 0.018, or HR = 3.86; 95% CI = 1.50-9.92; P = 0.005), respectively, compared with the CC genotype. Moreover, Lys/Gln+Gln/Gln genotypes of XPD Lys751Gln polymorphism were also associated with a significantly decreased RIET risk (adjusted HR = 0.55; 95% CI = 0.32-0.96; P = 0.030). Conclusions: This report, for the first time, examined the influence of inherited variation in the DNA repair and the cytokine pathways on RIET. © 2010 Elsevier Ireland Ltd. All rights reserved.

DOI 10.1016/j.radonc.2010.08.015
Citations Scopus - 33
2010 Li J, Wang W, Baines KJ, Bowden NA, Hansbro PM, Gibson PG, et al., 'IL-27/IFN-y induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages', Journal of Immunology, 185 4401-4409 (2010) [C1]
DOI 10.4049/jimmunol.1001039
Citations Scopus - 65Web of Science - 61
Co-authors Paul Foster, Philip Hansbro, Peter Gibson, Katherine Baines, Nikola Bowden
2010 Bi N, Yang M, Zhang L, Chen X, Ji W, Ou G, et al., 'Cyclooxygenase-2 genetic variants are associated with survival in unresectable locally advanced non-small cell lung cancer', Clinical Cancer Research, 16 2383-2390 (2010)

Purpose: Cyclooxygenase-2 (COX-2) plays important roles in the modulation of apoptosis, angiogenesis, immune response, and tumor invasion. Elevated COX-2 expression has been repor... [more]

Purpose: Cyclooxygenase-2 (COX-2) plays important roles in the modulation of apoptosis, angiogenesis, immune response, and tumor invasion. Elevated COX-2 expression has been reported to be correlated with reduced survival after radiotherapy. This study examined whether genetic variations in the COX-2 gene are associated with different survival in inoperable locally advanced non-small cell lung cancer (NSCLC) treated with chemoradiotherapy or radiotherapy alone. Experimental Design: One hundred and thirty-six patients with inoperable stage IIIA-B NSCLC receiving thoracic irradiation between 2004 and 2007 were recruited in this study. Five functional COX-2 polymorphisms were genotyped using DNA from blood lymphocytes. Kaplan-Meier methods were used to compare survival by different genotypes. Cox proportional hazards models were used to identify independently significant variables. Results: During the median 22.4 months of follow-up, the favorable COX-2 -1195GA and GG genotypes were significantly correlated with better overall survival (20.2 months versus 15.7 months; P = 0.006; hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.39-0.86) and with longer progress-free survival (11.9 months versus 9.5 months; P = 0.034) compared with the -1195AA genotype. No significant associations were found among other COX-2 polymorphisms and clinical outcomes. In the multivariate Cox proportional hazards model, COX-2 -1195G/A polymorphism was independently associated with overall survival after adjusting the clinicopathologic factors (P = 0.008; HR, 0.58; 95% CI, 0.39-0.87). Conclusion: COX-2 -1195G/A polymorphism is a potential predictive marker of survival in locally advanced NSCLC patients treated with chemoradiotherapy or radiotherapy alone. ©2010 AACR.

DOI 10.1158/1078-0432.CCR-09-2793
Citations Scopus - 29
2010 Sun T, Lee GSM, Oh WK, Pomerantz M, Yang M, Xie W, et al., 'Single-nucleotide polymorphisms in p53 pathway and aggressiveness of prostate cancer in a caucasian population', Clinical Cancer Research, 16 5244-5251 (2010)

Purpose: The tumor suppressor p53 plays a crucial role in maintaining genomic stability and tumor prevention. Mdm2, Mdm4, and Hausp are all critical regulators of the p53 protein.... [more]

Purpose: The tumor suppressor p53 plays a crucial role in maintaining genomic stability and tumor prevention. Mdm2, Mdm4, and Hausp are all critical regulators of the p53 protein. Despite the importance of the p53 pathway in prostate cancer development and progression, little is known about the association of functional single-nucleotide polymorphisms (SNP) in the p53 pathway genes and prostate cancer aggressiveness. Experimental Design: In this study, we analyze the association of SNPs in p53, Mdm2, Mdm4, and Hausp genes with prostate cancer clinicopathologic variables in a large hospital-based Caucasian prostate cancer cohort (N = 4,073). Results: We found that the Mdm2 SNP309 T allele was associated with earlier onset prostate cancer (P = 0.004), higher Gleason scores (P = 0.004), and higher stages in men undergoing a radical prostatectomy (P = 0.011). Both the Mdm4 and Hausp SNPs (rs1380576 and rs1529916) were found to be associated with higher D'Amico risk prostate cancer category at the time of diagnosis (P = 0.023 and P = 0.046, respectively). Mdm4 SNP was also found to be associated with higher Gleason score at radical prostatectomy (P = 0.047). We did not observe any statistically significant association between the p53 Arg72Pro polymorphism and prostate cancer aggressiveness or pathologic variables. Conculsions: These results suggested the importance of these p53 regulators in prostate cancer development and progression. ©2010 AACR.

DOI 10.1158/1078-0432.CCR-10-1261
Citations Scopus - 23
2010 Yang M, Kumar RK, Foster PS, 'Interferon-Y and pulmonary macrophages contribute to the mechanisms underlying prolonged airway hyperresponsiveness', Clinical and Experimental Allergy, 40 163-173 (2010) [C1]
DOI 10.1111/j.1365-2222.2009.03393.x
Citations Scopus - 27Web of Science - 22
Co-authors Paul Foster
2010 Hardy CL, Lemasurier JS, Olsson F, Dang T, Yao J, Yang M, et al., 'Interleukin-13 regulates secretion of the tumor growth factor-beta superfamily cytokine activin A in allergic airway inflammation', American Journal of Respiratory Cell and Molecular Biology, 42 667-675 (2010) [C1]
DOI 10.1165/rcmb.2008-0429OC
Citations Scopus - 20Web of Science - 19
2010 Wang W, Li J, Foster PS, Hansbro PM, Yang M, 'Potential therapeutic targets for steroid-resistant asthma', Current Drug Targets, 11 957-970 (2010) [C1]
DOI 10.2174/138945010791591412
Citations Scopus - 40Web of Science - 42
Co-authors Philip Hansbro, Paul Foster
2009 Sun T, Yang M, Kantoff P, Lee GSM, 'Role of microRNA-221/-222 in cancer development and progression', Cell Cycle, 8 2315-2316 (2009)
DOI 10.4161/cc.8.15.9221
Citations Scopus - 15
2009 Yang M, Kumar RK, Foster PS, 'Pathogenesis of steroid-resistant airway hyperresponsiveness: Interaction between IFN-gamma and TLR4/MyD88 pathways', Journal of Immunology, 182 5107-5115 (2009) [C1]
DOI 10.4049/jimmunol.0803468
Citations Scopus - 57Web of Science - 50
Co-authors Paul Foster
2009 Chen H, Yu D, Luo A, Tan W, Zhang C, Zhao D, et al., 'Functional role of S100A14 genetic variants and their association with esophageal squamous cell carcinoma', Cancer Research, 69 3451-3457 (2009)

S100 proteins have been implicated in various human diseases, including certain types of cancer. Among them, S100A14 is down-regulated in esophageal squamous cell carcinoma (ESCC)... [more]

S100 proteins have been implicated in various human diseases, including certain types of cancer. Among them, S100A14 is down-regulated in esophageal squamous cell carcinoma (ESCC). In this study, we sought to identify functional genetic variants in the S100A14 locus and assessed their associations with susceptibility to ESCC. Thirty individual DNA samples were sequenced to search for genetic variations in S100A14, and the function of the variants was investigated by a set of biochemical assays. A case-control analysis was performed in 1,021 patients with ESCC and 1,253 control subjects. Odds ratios and 95% confidence intervals (95% CI) were computed by logistic regression model. Eour single nucleotide polymorphisms, -43A>G, 461G>A, 1493A>G, and 1545A>T, were identified in the S100A14 locus and they are in absolute linkage disequilibrium. Among them, the 461G>A change was shown to diminish a P53-binding site and is therefore associated with decreased expression of S100A14 in vitro and in vivo in the target tissues. Case-control analysis showed that the 461A allele was associated with susceptibility to ESCC among smokers, with the ORs being 2.01 (95% CI, 1.50-2.69) or 2.10 (95% CI, 1.37-3.22) for the 461GA or 461AA genotype, respectively, compared with the 461GG genotype. These data constitute strong evidence in support of the notion that S100A14 might function as a cancer suppressor working in the P53 pathway and play a role in esophageal carcinogenesis. © 2009 American Association for Cancer Research.

DOI 10.1158/0008-5472.CAN-08-4231
Citations Scopus - 21
2009 Wu C, Wang G, Yang M, Huang L, Yu D, Tan W, Lin D, 'Two genetic variants in prostate stem cell antigen and gastric cancer susceptibility in a Chinese population', Molecular Carcinogenesis, 48 1131-1138 (2009)

Genetic factors play important roles in pathogenesis of human cancer. A recent genome-wide association study (GWAS) linked two single nucleotide polymorphisms (SNPs) in prostate s... [more]

Genetic factors play important roles in pathogenesis of human cancer. A recent genome-wide association study (GWAS) linked two single nucleotide polymorphisms (SNPs) in prostate stem cell antigen (PSCA), rs2294008C>T and rs2976392G>A, to risk of diffuse-type of gastric cancer in Japanese and Korean populations. We hypothesized that these two SNPs are also associated with risk of gastric cancer in Chinese population. We examined genotypes and haplotypes of PSCA, rs2294008C/T and rs2976392G/A in 716 patients with cardia gastric carcinoma (CGC), 1020 patients with noncardia gastric carcinoma (NCGC), and 1020 controls. We found that individuals with at least one copy of the rs2294008T allele (CT or TT genotype) had an elevated risk for developing NCGC compared with those without this allele (OR = 1.35, 95% CI = 1.13-1.61). Individuals with at least one copy of the rs2976392A allele (GA or AA genotype) had nonsignificantly increased risk for NCGC compared with those without this allele (OR = 1.20, 95% CI = 1.01-1.43). Stratification analysis showed that the increased risk associated with the SNPs was restricted in female subjects. Moreover, the rs2294008T and rs2976392A allele carriers were predisposed to developing poorly differentiated and high stage NCGC at diagnosis. However, no such association was detected for CGC. In addition, we observed considerably lower allelic and genotype frequencies of these genetic variants in Chinese population compared with Japanese and Korean populations. These findings are in general consistent with previous GWAS and suggest that PSCA may play a role in the development of NCGC in Chinese population. © 2009 Wiley-Liss, Inc.

DOI 10.1002/mc.20565
Citations Scopus - 42
2009 Yang M, Guo H, Wu C, He Y, Yu D, Zhou L, et al., 'Functional FEN1 polymorphisms are associated with DNA damage levels and lung cancer risk', Human Mutation, 30 1320-1328 (2009)

Flap endonuclease 1 (FEN1) is a key enzyme in maintaining genomic stability and protecting against carcinogenesis. This study investigated whether functional variations in FEN1 ge... [more]

Flap endonuclease 1 (FEN1) is a key enzyme in maintaining genomic stability and protecting against carcinogenesis. This study investigated whether functional variations in FEN1 gene are associated with DNA damage and lung cancer risk. Thirty DNA samples were sequenced to identify variants and function of the variants was examined by a set of biochemical assays. DNA damage levels were detected by comet assays in a cohort of 303 coke-oven workers and 297 controls. The association with lung cancer risk was examined in two independent case-control panels consisted of a total 1,840 lung cancer patients and 1,958 controls. We identified two single nucleotide polymorphisms (SNPs) located in the FEN1 promoter c.-69G>A (rs174538:G>A) and 3'-untranslational region c.4150G>T (rs4246215:G>T) that were associated with reduced FEN1 expression. Among cokeoven workers, DNA damage levels were significantly higher in the -69GG or GA carriers compared with the -69AA carriers. The -69GG or 4150GG carriers had a significantly increased risk for developing lung cancer compared with the -69AA or 4150TT carriers. These results highlight FEN1 as an important gene in human carcinogenesis and genetic polymorphisms in FEN1 confer susceptibility to lung cancer. © 2009 Wiley-Liss, Inc.

DOI 10.1002/humu.21060
Citations Scopus - 43
2008 Yu D, Zhang X, Liu J, Yuan P, Tan W, Guo Y, et al., 'Characterization of functional excision repair cross-complementation group 1 variants and their association with lung cancer risk and prognosis', Clinical Cancer Research, 14 2878-2886 (2008)

Purpose: The excision repair cross-complementation group 1 (ERCC1) plays a pivotal role in DNA repair and has been linked to protection against carcinogenesis and resistance to pl... [more]

Purpose: The excision repair cross-complementation group 1 (ERCC1) plays a pivotal role in DNA repair and has been linked to protection against carcinogenesis and resistance to platinum-based anticancer drugs. We tested whether genetic variants in the ERCC1 gene are associated with susceptibility to lung cancer and efficacy of platinum-chemotherapy in patients with small cell lung cancer (SCLC). Experimental Design: Thirty individual DNA samples were sequenced to search for single-nucleotide polymorphisms, and the functions of the variants were investigated by a series of biochemical assays. A case-control study was done in 988 patients with lung cancer and 986 control subjects. According to the genotypes, a comparison of chemotherapy outcome in 162 SCLC patients was executed. Overall survival was computed by Cox model adjusted for clinical factors. Results: We identified two functional variants in the ERCC1 5'-flanking region, -433T>C and 262G>T, which cooperatively influence transcriptional regulation of ERCC1. The 262G allele had significantly lower affinity to bind nuclear protein(s) and was associated with decreased ERCC1 RNA expression. The case-control analysis showed that the -433C and 262G alleles are associated with an increased susceptibility to lung cancer, alone and in a gene-smoking joint effect manner. In contrast, the analysis of chemotherapy outcome of SCLC patients revealed that the 262G allele is associated with better drug response and longer survival time compared with the 262Tallele. Conclusions: These findings are consistent with the notion that DNA repair is a double-edged sword in cancer and suggest that functional single-nucleotide polymorphisms in ERCC1 might serve as simple and less invasive biomarkers for personalized chemotherapy of platinum-based anticancer drugs. © 2008 American Association for Cancer Research.

DOI 10.1158/1078-0432.CCR-07-1612
Citations Scopus - 41
2008 Yang M, Sun T, Wang L, Yu D, Zhang X, Miao X, et al., 'Functional variants in cell death pathway genes and risk of pancreatic cancer', Clinical Cancer Research, 14 3230-3236 (2008)

Purpose: Fas-Fas ligand (FasL)-mediated death pathway is important in the life and death of immune cells and, therefore, influences immune surveillance of carcinogenesis. This stu... [more]

Purpose: Fas-Fas ligand (FasL)-mediated death pathway is important in the life and death of immune cells and, therefore, influences immune surveillance of carcinogenesis. This study examined the association between functional variants of Fas (-1377G ¿A and -670A¿G), FasL (-844T¿C), and caspase-8 (CASP8) six-nucleotide deletion polymorphism (-652 6N ins¿del) and risk of pancreatic cancer. Experimental Design: Genotypes were determined in 397 cases with pancreatic cancer and 907 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression, and all statistical tests were two sided. Results: We found a significant decrease in risk of pancreatic cancer associated with FasL and CASP8 but not Fas polymorphisms. Compared with noncarriers, the ORs of developing pancreatic cancer for FasL -844CT and TT carriers were 0.73 (95% CI, 0.57-0.94) and 0.35 (95% CI, 0.19-0.63), and for CASP8 -652 6N ins/del and del/del carriers were 0.65 (95% CI, 0.50-0.85) and 0.56 (95% CI, 0.33-0.98), respectively. Gene-gene interaction between the FasL and CASP8 variants further reduced the cancer risk in a multiplicative manner (OR for the presence of both FasL -844TTand CASP8 -652 6N del/del genotype, 0.10; 95% CI, 0.01-0.75). On the other hand, a multiplicative joint effect between the FasL -844CC or CASP8 -652 6N ins/ins genotype and smoking or diabetes mellitus in intensifying risk of pancreatic cancer was also evident. Conclusions: These results suggest that genetic variations in the death pathway genes FasL and CASP8 are involved in susceptibility to developing pancreatic cancer. © 2008 American Association for Cancer Research.

DOI 10.1158/1078-0432.CCR-08-0177
Citations Scopus - 69
2008 Sun T, Zhou Y, Yang M, Hu Z, Tan W, Han X, et al., 'Functional genetic variations in cytotoxic T-lymphocyte antigen 4 and susceptibility to multiple types of cancer', Cancer Research, 68 7025-7034 (2008)

Antitumor T lymphocytes play a pivotal role in immunosurveillance of malignancy. The CTL antigen 4 (CTLA-4) is a vital negative regulator of T-cell activation and proliferation. T... [more]

Antitumor T lymphocytes play a pivotal role in immunosurveillance of malignancy. The CTL antigen 4 (CTLA-4) is a vital negative regulator of T-cell activation and proliferation. This study examined whether genetic polymorphisms in CTLA-4 are associated with cancer susceptibility. A two-stage investigation using haplotype-tagging single nucleotide polymorphism approach and multiple independent case-control analyses was performed to assess the association between CTLA-4 genotypes and cancer risk. Functional relevance of the polymorphisms was examined by biochemical assays. We found that the 49G>A polymorphism in the CTLA-4 leading sequence causing17Ala to17Thr amino acid substitution is associated with increased susceptibility to multiple cancers, including lung, breast, esophagus, and gastric cardia cancers. Genotyping in 5,832 individuals with cancer and 5,831 control subjects in northern and southern Chinese populations showed that the CTLA-4 49AA genotype had an odds ratio of 1.72 (95% confidence interval, 1.50-2.10; P = 3.4 × 10-7) for developing cancer compared with the 49GG genotype. Biochemical analyses showed that CTLA-4-17Thr had higher capability to bind B7.1 and stronger inhibitory effect on T-cell activation compared with CTLA-4-17Ala. T cells carrying the 49AA genotype had significantly lower activation and proliferation rates compared with T cells carrying the 49GG genotype upon stimulation. These results are consistent with our hypothesis and indicate that genetic polymorphisms influencing T-cell activation modify cancer susceptibility. ©2008 American Association for Cancer Research.

DOI 10.1158/0008-5472.CAN-08-0806
Citations Scopus - 99
2008 Sun T, Gao Y, Tan W, Ma S, Shi Y, Yao J, et al., 'Reply to: A promoter polymorphism in the CASP8 gene is not associated with cancer risk', Nature Genetics, 40 260-261 (2008)
DOI 10.1038/ng0308-260
Citations Scopus - 1
2008 Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, et al., 'Overexpression and hypomethylation of Flap endonuclease 1 gene in breast and other cancers', Molecular Cancer Research, 6 1710-1717 (2008)

Flap endonuclease 1 (FEN1) is a structure-specific nuclease best known for its critical roles in Okazaki fragment maturation, DNA repair, and apoptosis-induced DNA fragmentation. ... [more]

Flap endonuclease 1 (FEN1) is a structure-specific nuclease best known for its critical roles in Okazaki fragment maturation, DNA repair, and apoptosis-induced DNA fragmentation. Functional deficiencies in FEN1, in the forms of somatic mutations and polymorphisms, have recently been shown to lead to autoimmunity, chronic inflammation, and predisposition to and progression of cancer. To explore how FEN1 contributes to cancer progression, we examined FEN1 expression using 241 matched pairs of cancer and corresponding normal tissues on a gene expression profiling array and validated differential expression by quantitative real-time PCR and immunohistochemistry. Furthermore, we defined the minimum promoter of human FEN1 and examined the methylation statuses of the 5' region of the gene in paired breast cancer tissues. We show that FEN1 is significantly up-regulated in multiple cancers and the aberrant expression of FEN1 is associated with hypomethylation of the CpG island within the FEN1 promoter in tumor cells. The overexpression and promoter hypomethylation of FEN1 may serve as biomarkers for monitoring the progression of cancers. Copyright © 2008 American Association for Cancer Research.

DOI 10.1158/1541-7786.MCR-08-0269
Citations Scopus - 57
2008 Yang M, Mattes J, 'Discovery, biology and therapeutic potential of RNA interference, microRNA and antagomirs', Pharmacology & Therapeutics, 117 94-104 (2008) [C1]
DOI 10.1016/j.pharmthera.2007.08.004
Citations Scopus - 73Web of Science - 67
Co-authors Joerg Mattes
2007 Mattes J, Yang M, Foster PS, 'Regulation of microRNA by antagomirs: a new class of pharmacological antagonists for the specific regulation of gene function?', American Journal of Respiratory and Cellular Molecular Biology, 36 8-12 (2007) [C1]
DOI 10.1165/rcmb.2006-0227TR
Citations Scopus - 58Web of Science - 50
Co-authors Joerg Mattes, Paul Foster
2007 Tan W, Wu J, Zhang X, Guo Y, Liu J, Sun T, et al., 'Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer', Carcinogenesis, 28 1197-1201 (2007)

Aberrant arachidonic acid metabolism by cyclooxygenase (COX)-2 and 12-lipoxygenase (LOX) has implicated in carcinogenesis. Genetic polymorphisms in COX-2 and 12-LOX might therefor... [more]

Aberrant arachidonic acid metabolism by cyclooxygenase (COX)-2 and 12-lipoxygenase (LOX) has implicated in carcinogenesis. Genetic polymorphisms in COX-2 and 12-LOX might therefore affect susceptibility to colorectal cancer (CRC). To examine this hypothesis, genotypes of COX-2 and 1290A>G, -1195G>A, -765G>C and 12-LOX 261Arg>Gln polymorphisms were determined in 1000 CRC patients and 1300 controls. Increased risk of developing CRC was associated with the COX-2-1195GA [adjusted odds ratio (OR) = 1.24, 95% confidence interval (CI) = 1.00-1.54] and -1195AA (adjusted OR = 1.77, 95% CI = 1.38-2.25) genotypes compared with the =1195GG genotype. Similarly, the increased risk for CRC was also associated with the COX-2 -765GC genotype (adjusted OR = 1.73, 95% CI = 1.23-2.43) compared with the -765GG genotype. Consistent with the results of genotype analyses, the ORs for the A-1195-C-765-containing haplotypes were significantly higher than those for the G-1195-G-765-containing haplotypes (P < 0.01). Furthermore, the -1195A allele was further associated with advanced CRC, with adjusted ORs of Dukes D CRC against Dukes A CRC being 2.43 (95% CI = 1.15-4.97) and 2.66 (95% CI = 1.23-5.74) for the -1195GA and -1195AA genotypes, respectively. The increased risk of CRC was also associated with the 12-LOX 261Gln/Gln genotype compared with the Arg/Arg genotype (adjusted OR = 1.38, 95% CI = 1.09-1.74). Together, these observations indicate that inherited polymorphisms in arachidonic acid-metabolizing enzymes may confer susceptibility to CRC. © The Author 2006. Published by Oxford University Press. All rights reserved.

DOI 10.1093/carcin/bgl242
Citations Scopus - 67
2007 Yang M, Guo Y, Zhang X, Miao X, Tan W, Sun T, et al., 'Interaction of P53 Arg72Pro and MDM2 T309G polymorphisms and their associations with risk of gastric cardia cancer', Carcinogenesis, 28 1996-2001 (2007)

The P53 tumor suppressor pathway plays an important role in cancer development. The auto-regulatory feedback mechanism of the P53 and MDM2 expression is critical in keeping proper... [more]

The P53 tumor suppressor pathway plays an important role in cancer development. The auto-regulatory feedback mechanism of the P53 and MDM2 expression is critical in keeping proper tumor suppressor function of this pathway. This study examined the effect of P53 Arg72Pro variants on transactivation of polymorphic MDM2 promoter (T309G) and their associations with risk of developing gastric cardia adenocarcinoma (GCA) in a Chinese population. Luciferase assays consistently showed a significantly higher activity of the MDM2 309G promoter compared with the MDM2 309T promoter. In cells co-transfected with variant P53 cDNAs, P53-72Pro displayed a significantly higher ability to activate the MDM2 promoter than P53-72Arg. Genotype analyses in 500 GCA patients and 1000 controls showed that significantly increased risk for developing GCA was associated with the MDM2 309G and the P53 72Pro allele compared with the MDM2 309T and the P53 72Arg allele in an allele dose-dependent manner. A joint effect between the MDM2 and P53 polymorphisms in intensifying GCA risk was detected, with the odds ratio (OR) for the presence of both MDM2 390GG and P53 72Pro/Pro genotypes being 5.05 [95% confidence interval (CI), 2.50-10.20]. These results suggest that the P53 72Pro and MDM2 309G polymorphisms contribute to the risk of developing GCA. © The Author 2007. Published by Oxford University Press. All rights reserved.

DOI 10.1093/carcin/bgm168
Citations Scopus - 59
2007 Sun T, Gao Y, Tan W, Ma S, Shi Y, Yao J, et al., 'A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers', Nature Genetics, 39 605-613 (2007)

Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies. We tested whether genetic variants in CASP8, CASP10 and C... [more]

Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies. We tested whether genetic variants in CASP8, CASP10 and CFLAR, three genes important for death receptor-induced cell killing residing in tandem order on chromosome 2q33, are associated with cancer susceptibility. Using a haplotype-tagging SNP approach, we identified a six-nucleotide deletion (-652 6N del) variant in the CASP8 promoter associated with decreased risk of lung cancer. The deletion destroys a stimulatory protein 1 binding site and decreases CASP8 transcription. Biochemical analyses showed that T lymphocytes with the deletion variant had lower caspase-8 activity and activation-induced cell death upon stimulation with cancer cell antigens. Case-control analyses of 4,995 individuals with cancer and 4,972 controls in a Chinese population showed that this genetic variant is associated with reduced susceptibility to multiple cancers, including lung, esophageal, gastric, colorectal, cervical and breast cancers, acting in an allele dose-dependent manner. These results support the hypothesis that genetic variants influencing immune status modify cancer susceptibility. © 2007 Nature Publishing Group.

DOI 10.1038/ng2030
Citations Scopus - 174
2007 Zhao D, Sun T, Zhang X, Guo Y, Yu D, Yang M, et al., 'Role of CD14 promoter polymorphisms in Helicobacter pylori infection - Related gastric carcinoma', Clinical Cancer Research, 13 2362-2368 (2007)

Purpose: Genetic variation in CD14 may affect CD14 expression and susceptibility to Helicobacter pylori infection - related cancers. This study examined functional single nucleoti... [more]

Purpose: Genetic variation in CD14 may affect CD14 expression and susceptibility to Helicobacter pylori infection - related cancers. This study examined functional single nucleotide polymorphisms (SNP) in the CD14 promoter and their associations with risk of developing gastric carcinoma in relation to H. pylori infection. Experimental Design: Thirty individual DNAs were sequenced to identify variants, and the function of the variants was examined by reporter gene assays. Genotypes and haplotypes were analyzed in 470 patients and 470 controls, and odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression. Serologic H. pylori antibody and soluble CD14 (sCD14) levels were measured by ELISA. Results: Two SNPs (-651C>T and -260C>T) were identified, of which the -260CT and -260TT genotypes were associated with elevated risk of gastric carcinoma (OR, 1.77; 95% CI, 1.09-2.85 and OR, 1.95; 95% CI, 1.20-3.16, respectively). Haplotype analysis suggested a synergistic effect of the two SNPs (OR for the T-651-T-260haplotype, 3.39 versus OR for the C-651-T-260haplotype, 1.45; P = 0.02), which is consistent with reporter gene assays. A multiplicative joint effect between H. pylori infection and -260C>T polymorphism was observed (OR for the presence of both -260TT genotype and H. pylori infection, 4.03; 95% CI, 1.80-9.04). Patients had significantly higher sCD14 than controls (1,866 ± 2,535 ng/mL versus 1,343 ± 2,119 ng/mL; P < 0.001), and this difference was associated with the CD14 -260 polymorphism and H. pylori infection. Conclusions: Functional polymorphism in CD14 is associated with greater risk of H. pylori - related gastric carcinoma, which might be mediated by elevated sCD14. © 2007 American Association for Cancer Research.

DOI 10.1158/1078-0432.CCR-06-2612
Citations Scopus - 37
2007 Webb DC, Yang M, Matthaei (Ext) K, Foster PS, 'Comparative roles of IL-4, IL-13, and IL-4Ralpha in dendritic cell maturation and CD4+ Th2 cell function', Journal of Immunology, 178 219-227 (2007) [C1]
Citations Scopus - 51Web of Science - 50
Co-authors Paul Foster
2006 Yang M, Rangasamy D, Matthaei KI, Frew AJ, Zimmmermann N, Mahalingam S, et al., 'Inhibition of arginase I activity by RNA interference attenuates IL-13-induced airways hyperresponsiveness', Journal of Immunology, 177 5595-5603 (2006) [C1]
DOI 10.4049/jimmunol.177.8.5595
Citations Scopus - 84Web of Science - 75
Co-authors Paul Foster
2006 Yang M, Mattes J, Hansbro PM, Foster PS, 'Employment of microRNA profiles and RNA interference and antagomirs for the characterization and treatment of respiratory disease', Drug Discovery Today: Therapeutic Strategies, 3 325-332 (2006) [C1]
DOI 10.1016/j.ddstr.2006.10.001
Citations Scopus - 5
Co-authors Joerg Mattes, Philip Hansbro, Paul Foster
2006 Yang M, Rangasamy D, Matthaei K, Frew A, Zimmmermann N, Mahalingham S, et al., 'Inhibition of arginase I activity by RNA interference attenuates interleukin-13 induced airways hyperresponsiveness', ACTA PHARMACOLOGICA SINICA, 27 266-266 (2006)
Co-authors Paul Foster
2006 Siegle JS, Hansbro NG, Herbert C, Yang M, Foster PS, Kumar RK, 'Airway hyperreactivity in exacerbation of chronic asthma is independent of elosinophilic inflammation', American Journal of Respiratory Cell and Molecular Biology, 35 565-570 (2006) [C1]
DOI 10.1165/rcmb.2006-0135OC
Citations Scopus - 46Web of Science - 43
Co-authors Nicole Hansbro, Paul Foster
2004 Forbes E, Smart V, D'Aprile A, Henry P, Yang M, Matthaei KI, et al., 'T Helper-2 Immunity Regulates Bronchial Hyperresponsiveness in Eosinophil-Associated Gastrointestinal Disease in Mice', Gastroenterology, 127 105-118 (2004) [C1]
DOI 10.1053/j.gastro.2004.03.057
Citations Scopus - 15Web of Science - 18
Co-authors Paul Foster
2004 Forbes E, Murase T, Yang M, Matthaei KI, Lee JJ, Lee NA, et al., 'Immunopathogenesis of experimental ulcerative colitis is mediated by eosinophil peroxidase1', J Immunol, 172 5664-5675 (2004) [C1]
Citations Scopus - 108Web of Science - 94
Co-authors Paul Foster
2004 Fulkerson PC, Zimmermann N, Brandt EB, Muntel EE, Doepker MP, Kavanaugh JL, et al., 'Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by INF-g (Mig, CXCL9)', Proceedings of the National Academy of Sciences of the USA, 101 1987-1992 (2004) [C1]
DOI 10.1073/pnas.0308544100
Citations Scopus - 77Web of Science - 73
Co-authors Paul Foster
2003 Foster PS, Yang M, Mattes J, Kumar R, Webb D, 'Interleukin-13 and allergy', Modern Aspects of Immunobiology, 3 8 (2003)
Co-authors Paul Foster, Joerg Mattes
2003 Zimmerman N, King NE, Laporte J, Yang M, Mishra A, Pope S, et al., 'Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis', Journal of Clinical Investigation, 111 1863-1874 (2003) [C1]
DOI 10.1172/JCI200317912
Citations Scopus - 408Web of Science - 378
Co-authors Paul Foster
2003 Kumar RK, Herbert C, Thomas PS, Wollin L, Beume R, Yang M, et al., 'Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma', Journal of Pharmacology and Experimental Therapeutics, 307 349-355 (2003) [C1]
DOI 10.1124/jpet.103.053819
Citations Scopus - 132Web of Science - 107
Co-authors Paul Foster
2003 Yang M, Hogan SP, Mahalingam S, Pope SM, Zimmerman N, Fulkerson P, et al., 'Eotaxin-2 and IL-5 cooperate in the lung to regulate IL-13 production and airway eosinophilia and hyperreactivity', Journal of Allergy and Clinical Immunology, 112 935-943 (2003) [C1]
DOI 10.1016/j.jaci.2003.08.010
Citations Scopus - 87
Co-authors Paul Foster
2003 Foster PS, Webb DC, Yang M, Herbert C, Kumar RK, 'Dissociation of T helper type 2 cytokine-dependent airway lesions from signal transducer and activator of transcription 6 signalling in experimental chronic asthma', Clinical and Experimental Allergy, 33 688-695 (2003) [C1]
DOI 10.1046/j.1365-2222.2003.01647.x
Citations Scopus - 46Web of Science - 42
Co-authors Paul Foster
2002 Mattes J, Yang M, Mahalinggam S, Kuehr J, Webb DC, Simson L, et al., 'Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and cotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma.', J Exp Med. 195:1433-44, 1433-1444 (2002) [C1]
Citations Scopus - 205Web of Science - 189
Co-authors Paul Foster, Joerg Mattes
2002 Foster PS, Yang M, Herbert C, Kumar R, 'CD4+ T-lymphocytes regulate airway remodeling and hyper-reactivity in a mouse model of chronic asthma', Laboratory Investigation, 82 455-462 (2002) [C1]
Citations Web of Science - 45
Co-authors Paul Foster
2002 Foster PS, Hogan S, Yang M, Mattes J, Young I, Matthaei K, et al., 'Interleukin-5 and eosinophils as therapeutic targets for asthma', Trends in Molecular Medicine, 8 162-167 (2002) [C2]
Citations Scopus - 61Web of Science - 55
Co-authors Paul Foster, Joerg Mattes
2002 Kumar R, Herbert C, Yang M, Koskinen A, McKenzie A, Foster PS, 'Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma', Clinical and Experimental Allergy, 32 1104-1111 (2002) [C1]
Citations Scopus - 139Web of Science - 114
Co-authors Paul Foster
2002 Foster PS, Yang M, Herbert C, Kumar RK, 'CD4

Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma... [more]

Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma is associated with remodeling of the airway wall, which may contribute to hyper-reactivity and fixed airflow obstruction. We used an improved mouse model of chronic asthma to investigate the role of CD4+T-lymphocytes in airway remodeling and hyper-reactivity. Animals functionally depleted of CD4+T-lymphocytes by repeated administration of a monoclonal antibody exhibited markedly decreased airway responsiveness. In addition, these mice had greatly diminished subepithelial fibrosis, epithelial thickening, and mucous cell hyperplasia/metaplasia. Chronic inflammation in the airway wall was moderately reduced, with a marked decrease in the accumulation of immunoglobulin- synthesizing plasma cells. However, intraepithelial accumulation of eosinophils was not significantly inhibited and airway epithelial expression of eotaxin was undiminished. This work provides the first experimental evidence that CD4+T-lymphocytes play a crucial role in the pathogenesis of the lesions of chronic asthma and lends support to the notion that functional inhibition of these cells may be an important therapeutic target.

DOI 10.1038/labinvest.3780438
Citations Scopus - 41
Co-authors Paul Foster
2002 Yang M, Hogan SP, Henry P, Matthaei KI, McKenzie ANJ, Young IG, et al., 'Interleukin-(IL)-13 mediates biphasic airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 109 S360-S360 (2002)
DOI 10.1016/S0091-6749(02)82255-2
Co-authors Paul Foster
2001 Mattes J, Yang M, Siqueira A, Clark K, Mackenzie J, McKenzie A, et al., 'IL-13 induces airways hyperreactivity independently of the IL-4R{alpha} chain in the allergic lung', Journal of Immunology, 167 1683-1692 (2001) [C1]
Citations Scopus - 124Web of Science - 111
Co-authors Joerg Mattes, Paul Foster
2001 Foster PS, Mould A, Yang M, Mackenzie J, Mattes J, Hogan S, et al., 'Elemental signals regulating eosinophil accumulation in the lung', Immunological Reviews, 179 173-181 (2001) [C2]
Citations Scopus - 178Web of Science - 160
Co-authors Joerg Mattes, Paul Foster
2001 Yang M, Hogan S, Henry P, Matthaei K, McKenzie A, Young I, et al., 'Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin', American Journal of Respiratory Cell and Molecular Biology, 25 522-530 (2001) [C1]
Citations Scopus - 125Web of Science - 115
Co-authors Paul Foster
2000 Webb D, McKenzie A, Koskinen A, Yang M, Mattes J, Foster PS, 'Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity', Journal of Immunology, 165 108-113 (2000) [C1]
Citations Scopus - 239Web of Science - 222
Co-authors Paul Foster, Joerg Mattes
1998 Yang M, Cao Y, Mohapatra SS, 'CD8

In an effort to examine the basis for low IgE responsiveness of SJL/J strain mice, we analysed the profiles of cytokines, such as interleukin-2 (IL-2), IL-4 and interferon-¿ (IFN-... [more]

In an effort to examine the basis for low IgE responsiveness of SJL/J strain mice, we analysed the profiles of cytokines, such as interleukin-2 (IL-2), IL-4 and interferon-¿ (IFN-¿), in SJL/J and A.SW/SnJ mice following immunization. Splenocytes of ovalbumin (OVA) -immunized SJL/J mice, secreted significantly higher levels of IL-4 and lower levels of IFN-¿ than those of A.SW/SnJ mice. A time-course analysis of cytokine expression in in vitro cultures of spleen cells indicated that the levels of IL-4 and IL-2 remained persistently high throughout in the cultures of SJL/J splenocytes as opposed to those of A.SW/SnJ. Depletion of CD4+T cells in vivo suppressed the production of IL-2, IL-4 and IFN-¿ suggesting that CD4 T cells are the producers of most cytokines in both SJL/J and A.SW/SnJ mice. Depletion of CD8+T cells in vivo not only induced productive e transcript but also enhanced IgE production in SJL/J mice. Moreover, CD8 depletion in SJL/J mice led to decreased production of IFN-¿, resulting in a net decrease in the ratio of IFN-¿ to IL-4. A similar shift in the IFN-¿/IL-4 ratio was found in splenocytes of SJL/J mice following irradiation, which is known to enhance IgE synthesis in these mice. Taken together, it is concluded that low IgE responsiveness in SJL/J mice is not due to a defect in IL-4 production per se. Increased IFN-¿ production by the CD8+T cells inhibits class switch and suppresses IgE antibody production in SJL/J mice.

DOI 10.1046/j.1365-2567.1998.00415.x
Citations Scopus - 6
1997 Fan T, Yang M, Halayko A, Mohapatra SS, Stephens NL, 'Airway Responsiveness in Two Inbred Strains of Mouse Disparate in IgE and IL-4 Production', American Journal of Respiratory Cell and Molecular Biology, 17 156-163 (1997)

The mouse provides an excellent model for genetic studies of asthma, which is characterized by airway hyperexcitability and hyperreactivity. The former is a function of the proper... [more]

The mouse provides an excellent model for genetic studies of asthma, which is characterized by airway hyperexcitability and hyperreactivity. The former is a function of the properties of the membrane of the airway smooth muscle (ASM), whereas the latter is a function, albeit indirectly, of the mechanical properties of the muscle contractile apparatus. The very small size of the muscle has in the past hampered its study. We report herein that contractile properties of tracheal smooth muscle (TSM) can be measured in mice. We examined TSM strips from two inbred strains of mouse, ASW and SJL, which are high and low IgE responders, respectively. Force-velocity relationships were measured in four groups of mice, two ASW (control and sensitized) and two SJL (control and sensitized). Muscle strips from sensitized SJL mice exhibited shortening velocities (V0) and maximum shortening capacities (¿Lmax), that were significantly greater than those of the other groups. However, no difference was found between the two strains in maximal isometric force (P0). The two strains also showed differences in their potential to express cytokines such as interleukin-4 (IL-4) and IL-5 in ex vivo splenocyte cultures, as measured by the cytokines' messenger RNA (mRNA) and protein expression. The SJL strain, which exhibited TSM hyperreactivity, was found to produce significantly greater amounts of IL-4 than the ASW strain. We conclude that the altered contractile properties of TSM in sensitized SJL mice are independent of IgE response, but linked to increased amounts of IL-4.

DOI 10.1165/ajrcmb.17.2.2628
Citations Scopus - 66
1997 Cao Y, Yang M, Luo Z, Mohapatra SS, 'Vaccination with a multi-epitopic recombinant allergen induces specific immune deviation via T-cell anergy', Immunology, 90 46-51 (1997)

Prophylactic vaccination has recently emerged as a major paradigm toward the prevention and therapy of allergies and asthma; however, the immunological basis of this approach rema... [more]

Prophylactic vaccination has recently emerged as a major paradigm toward the prevention and therapy of allergies and asthma; however, the immunological basis of this approach remains to be elucidated. We examined the potential and mechanism of prophylaxis of allergic response in B6D2F1 mice with a multi-epitopic recombinant allergen, rKBG8.3 (MERA-8.3), which represents a major group of allergens of grass pollens, used herein as a model of MERA vaccine. Vaccination (subcutaneous) with soluble MERA-8.3, prior to immunization with the MERA-8.3 in alum, led to suppression of the IgE antibody response and a concomitant increase in IgG2a antibody response specific to the MERA-8.3 in a dose-dependent manner. Analysis of cytokine patterns in spleen and lymph node cells revealed a marked decrease of interleukin-2 (IL-2) and IL-4 production and to a lesser extent a decrease of interferon-¿ (IFN-¿) synthesis, resulting in an increased ratio of IFN-¿:IL-4 in vaccinated-immunized mice compared with untreated-immunized control mice. Furthermore, splenocytes of mice treated with the MERA-8.3 alone proliferated to MERA-8.3 in vitro with reduced capacity compared with the splenocytes of MERA-8.3-alum immunized mice, owing to a markedly reduced level of IL-2 production in the former. Collectively, these results suggest that vaccination with the MERA-8.3 induces T-cell anergy, which is pivotal to deviation of specific immunity from Th2- to Th1-like, and may serve as an important approach to prevention and therapy of allergic disorders.

DOI 10.1046/j.1365-2567.1997.00132.x
Citations Scopus - 11
1996 Yang M, Wang YY, Zhang L, Chong P, Mohapatra SS, 'Host genetic and adjuvant factors influence epitope specificity to a major recombinant grass allergen', International Archives of Allergy and Immunology, 111 173-181 (1996)

The role of host genetic and adjuvant factors in the induction of immune responses to a major recombinant Kentucky bluegrass allergen was examined utilizing five strains of mice a... [more]

The role of host genetic and adjuvant factors in the induction of immune responses to a major recombinant Kentucky bluegrass allergen was examined utilizing five strains of mice and two different adjuvants. Analysis of the recombinant allergen-specific antibodies induced in these strains indicated that the antibodies of various isotypes were differentially regulated. In terms of IgE antibody response, BDF1 and DBA/2 were characterized as high responder, whereas BALB/C, CBA/J and C57BL/6 were intermediate and SJL was a low responder. In different strains, both dextran sulfate (DS) and complete Freund¿s adjuvant (CFA), as adjuvants, induced recombinant allergen-specific IgE antibodies of similar titer, however, CFA induced higher IgG2a and lower IgM antibodies compared to DS. Further, analysis of T cell proliferative responses of the splenocytes of different strains demonstrated that these strains varied also in their capacity to respond to synthetic peptides. Furthermore, utilizing a panel of synthetic peptides corresponding to the recombinant allergen, we demonstrated that the antibodies induced by the recombinant allergen with CFA in different strains vary with respect to their epitope specificity. In the BDF1 strain, compared to DS, CFA as adjuvant induced recombinant allergen-specific antibodies of additional peptide specificity. Taken together, these results suggest that both host genetic background and adjuvants govern the fine specificity of antibodies produced against this recombinant Kentucky bluegrass allergen. © 1996 S. Karger AG, Basel.

DOI 10.1159/000237364
Citations Scopus - 4
1996 Peng Z, Yang M, Simons ER, Becker AB, 'Cross-Reactivity and Molecular Mass of the Chains of the IgE Antibodies in Dogs, Humans, Rats, and Mice', International Archives of Allergy and Immunology, 110 149-155 (1996)

We report the cross-reactivities and comparative molecular masses of the IgE e chains in humans, rats, mice, and dogs. Monoclonal human, rat, and mouse IgE, and our purified polyc... [more]

We report the cross-reactivities and comparative molecular masses of the IgE e chains in humans, rats, mice, and dogs. Monoclonal human, rat, and mouse IgE, and our purified polyclonal dog IgE were used in the study. IgE of the 4 species, separated by SDS-PAGE, were analyzed by immunoblotting with polyclonal and monoclonal antihuman IgE, polyclonal and monoclonal antimouse IgE, monoclonal antirat IgE, and polyclonal antidog IgE antibodies. The polyclonal anti-human and polyclonal antimouse IgE cross-reacted with the IgE of the other 3 species, while their monoclonal forms cross-reacted with dog IgE only. Polyclonal antidog IgE cross-reacted with human and mouse IgE, while the monoclonal antirat IgE did not cross-react with any other species. ¿Reverse¿ passive cutaneous anaphylaxis in ragweed-sensitized dogs revealed that polyclonal anti-human and polyclonal antimouse IgE were able to elicit positive skin responses, and monoclonal antihuman, antirat, and antimouse IgE antibodies were not. The molecular masses of the e chains were 77 kDa for mice, 75 kDa for rats and dogs, and 70 kDa for humans. © 1996 S. Karger AG, Basel.

DOI 10.1159/000237279
Citations Scopus - 6
1996 Peng Z, Yang M, Simons FER, 'Immunologic mechanisms in mosquito allergy: Correlation of skin reactions with specific IgE and IgG antibodies and lymphocyte proliferation response to mosquito antigens', Annals of Allergy, Asthma and Immunology, 77 238-244 (1996)

Background: Allergic reactions to mosquito bites are a common problem. Although IgE-mediated hypersensitivity has been reported, other immunologic mechanisms may be involved. Obje... [more]

Background: Allergic reactions to mosquito bites are a common problem. Although IgE-mediated hypersensitivity has been reported, other immunologic mechanisms may be involved. Objectives: To study the relationship between skin bite reactions and immunologic parameters. Methods: Forty-one subjects were experimentally exposed to mosquito (Aedes vexans) bites. Immediate and delayed skin reactions were traced at 20 minutes and 24 hours, respectively, after the bites. Sera were analyzed for mosquito salivary gland-specific IgE (mosquito-IgE) and IgG (mosquito-IgG) by ELISA. Lymphocyte proliferation assays with mosquito extract were also performed. Results: One of 41 subjects had only a delayed skin reaction to the bite, 23 had both immediate and delayed reactions, 6 had only immediate reactions, and 11 had no reaction. The mean mosquito-IgE and -IgG concentrations were higher in the subjects with immediate reactions than in those without immediate reactions (P < .007). The mean lymphocyte proliferation stimulation index was higher in the subjects with delayed reactions than in those without delayed reactions (P < .015). Further, both mosquito-IgE and -IgG levels correlated with skin immediate and delayed reactions (P < .04), while lymphocyte proliferation indices only correlated with skin delayed reactions (P < .006). Inverse correlations were found between the size of skin reactions and the number of years lived in Canada (P < .04), but not with age. Conclusion: These results indicate that IgE-, lymphocyte- and, probably, local IgG immune-complex- mediated hypersensitivities are involved in mosquito allergy. Naturally acquired desensitization to mosquito bites occurs during long-term exposure.

DOI 10.1016/S1081-1206(10)63262-0
Citations Scopus - 68
1996 Zhang L, Yang M, Chong P, Mohapatra SS, 'Multiple B- and T-cell epitopes on a major allergen of Kentucky Bluegrass pollen', Immunology, 87 283-290 (1996)

The B- and T-cell epitopes of a recombinant grass allergen, rKBG60, were delineated using a set of overlapping synthetic peptides. Direct binding by enzyme-linked immunosorbent as... [more]

The B- and T-cell epitopes of a recombinant grass allergen, rKBG60, were delineated using a set of overlapping synthetic peptides. Direct binding by enzyme-linked immunosorbent assay (ELISA) utilizing serum pools led to the identification of 13 murine immunoglobulin-, and nine to 13 human IgG- and five to seven human IgE-reactive overlapping peptides. Of the peptides which bound to human IgE antibodies, all but three peptides bound to human and/or murine IgG antibodies. Furthermore, eight out of 12 synthetic peptides induced antigen-specific antibodies in mice, suggesting that these peptides contained epitopes that recognized and/or induced T cells. These results, in conjunction with cross-recognition of different peptides at the C-terminus of rKBG60 by antibodies to neighbouring or non-overlapping peptides suggest that the C-terminus of this antigen represents a dominant antigenic and allergenic site. Peripheral blood mononuclear cell (PBMC) proliferation studies using these synthetic peptides for 13 grass allergic individuals indicated that seven potential human T-cell epitopes exist on this allergen. Taken together, the results demonstrate that multiple B- and T-cell epitopes exist on this major group of grass allergens, the majority of which are localized at the C-terminus of this antigen.

DOI 10.1046/j.1365-2567.1996.467533.x
Citations Scopus - 10
1995 Yang M, Becker AB, Simons FER, Peng Z, 'Identification of a dog IgD-like molecule by a monoclonal antibody', Veterinary Immunology and Immunopathology, 47 215-224 (1995)

IgD has not been identified in dogs. We produced a monoclonal antibody (mAb) designated 9B during the production of hybridomas to dog IgE. Using Western blot analysis under non-re... [more]

IgD has not been identified in dogs. We produced a monoclonal antibody (mAb) designated 9B during the production of hybridomas to dog IgE. Using Western blot analysis under non-reducing conditions, the mAb (9B) recognized a predominant protein band of 185 kDa which was also recognized by anti-dog IgG F(ab')2, suggesting that this 185 kDa protein is an immunoglobulin (Ig) containing light chains. Under reducing conditions, the mAb (9B) recognized only one protein band of 55 kDa which presented a distinct molecular weight (MW) and immunoreactivity from the dog t, µ, a, and e{lunate} chains. The 55 kDa band did not react with anti-dog IgE, IgM, IgA, and IgG, but did react with the mAb (9B). The MW was 75 kDa for the e{lunate} chain, 77.5 kDa for the µ chain, 58 kDa for the a chain, and 52 kDa for the t chain. Further, by immunofluorescent staining, this Ig recognized by the mAb (9B) was found on the surface of dog lymphocytes. Studies of this dog Ig with the mAb revealed that this Ig bound to protein A and protein G-Sepharose, and that its enzyme-linked immunosorbent assay (ELISA) activity as measured by the mAb (9B) did not change after heating at 56°C for 2 h. Ragweed-specific IgG, IgE, and this newly defined Ig significantly increased when dogs were immunized with ragweed extract. These data suggest that this Ig is a previously unrecognized IgD-like molecule in dogs. © 1995.

DOI 10.1016/0165-2427(94)05401-D
Citations Scopus - 6
1995 Venugopal G, Yang M, Luo Z, Salo D, Cheang M, Mohapatra SS, 'Analysis of Tcrvb8, Il4, and Ifg as genetic predisposition factors for atopic IgE response in a murine model', Journal of Immunology, 155 5463-5470 (1995)

Allergen-induced synthesis of IgE Abs in genetically predisposed individuals constitutes the hallmark of allergic diseases; however, the molecular basis of this genetic predisposi... [more]

Allergen-induced synthesis of IgE Abs in genetically predisposed individuals constitutes the hallmark of allergic diseases; however, the molecular basis of this genetic predisposition remains unknown. T cell cytokines IL-4 and IFN-¿ reciprocally regulate IgF synthesis and are potential genetic factors governing atopy. To examine the inheritance patterns of IgE responsiveness and address the role of these cytokines as genetic predisposition factors, in this study we established a MHC-identical mouse colony comprising crosses between two inbred strains of mouse, A.SW and SJL, respectively representing high and low IgE responder phenotypes. Segregation analysis with 149 [(A.SW x SJL)F1x SJL] backcross and 148 [(A.SW x SJL)F1x F1] F2mice suggested that persistent high IgE responsiveness was inherited as a simple Mendelian dominant trait under the control of a single non-MHC, autosomal gene of major effect in these strains. Since SJL lacked Tcrvb8 genes, we examined the possibility of Tcrvb8 as a candidate gene for IgE responsiveness. The results suggested association of neither the Tcrvb8 gene nor its expression with allergen-induced IgE phenotype. Furthermore, microsatellite marker and gene sequencing analyses revealed that neither of the Il4 and Ifg genes was associated with IgE phenotype. Moreover, correlation studies between IgE and cytokine levels in splenocyte cultures indicated that IgE levels were moderately to poorly correlated with IL-4 and IFN-¿ levels. It is concluded that even though expression of Tcrvb8, Il4, and Ifg genes may play pivotal roles in IgE regulation, these genes per se do not contribute to genetic predisposition of allergen-induced IgE hyperresponsiveness in these strains of mice.

Citations Scopus - 13
1994 Mohapatra SS, Mohapatra S, Yang M, Ansari AA, Parronchi P, Maggi E, Romagnani S, 'Molecular basis of cross-reactivity among allergen-specific human T cells: T-cell receptor Va gene usage and epitope structure', Immunology, 81 15-20 (1994)

Cross-reactivities between the major grass pollen allergens, at the level of T-cell recognition was examined employing several Lolium perenne I (Lol p I)-specific human T-cell clo... [more]

Cross-reactivities between the major grass pollen allergens, at the level of T-cell recognition was examined employing several Lolium perenne I (Lol p I)-specific human T-cell clones. Nine of these Lol p I-specific T-cell clones exhibited cross-recognition of the recombinant Poa pratensis IX (Poa p IX) allergen, rKBG7.2, indicating that these two major antigens of a grass pollen share T-cell epitopes. Furthermore, proliferative responses of two other T- cell clones demonstrated that individual allergens of diverse grass pollens also possess common T-cell epitopes. Examination of the T-cell receptor (TcR)Va genes of these T-cell clones indicated that these cloned cells utilized distinct Va genes and that nine out of 10 clones possessed Va13 gene. Furthermore, sequence comparisons of several allergenic molecules indicated that this cross-reactivity may be due to the presence of epitope(s) with structure(s) similar to the major T-cell epitope of Poa p IX allergens. Taken together, these results suggest for the first time that the major grass pollen allergens share cross-reacting T-cell epitope(s), and that this cross- reactivity is due to the structural homologies among allergens and restricted usage of TcR Va genes.

Citations Scopus - 37
1991 Yang M, Olsen E, Dolovich J, Sehon AH, Mohapatra SS, 'Immunologic characterization of a recombinant Kentucky (Poa pratensis) allergenic peptide', The Journal of Allergy and Clinical Immunology, 87 1096-1104 (1991)

A recombinant peptide of Kentucky bluegrass (KBG) pollen was synthesized as a fusion protein (FP) in Escherichia coli by recombinant DNA procedures and was compared with its natur... [more]

A recombinant peptide of Kentucky bluegrass (KBG) pollen was synthesized as a fusion protein (FP) in Escherichia coli by recombinant DNA procedures and was compared with its natural counterparts with respect to its allergenic properties. The FP was demonstrated to bind to the IgE antibodies (Abs) of =95% of 55 individual sera examined. A positive correlation (r = 0.90) was observed between the levels of IgE Abs corresponding to the FP and the grass-pollen extract(s). With sera of five allergic patients, the IgE binding of three different protein preparations were compared, namely, KBG pollen proteins, 27 to 35 kd gel-purified pollen proteins, and the FP. Results indicated that about 50% of the total IgE binding of KBG pollen proteins was due to the IgE Abs specific to FP. Comparison of the above protein preparations with respect to their abilities to specifically stimulate murine popliteal lymph node cells in vitro indicated that the total pollen proteins stimulated the highest proliferation of lymph node cells. Interestingly, the FP supported higher proliferation of lymph node cells than the gel-purified proteins. Collectively, these results suggest that the recombinant peptide constitutes a major allergenic constituent of grass pollens and may be of diagnostic and therapeutic value. © 1991.

DOI 10.1016/0091-6749(91)92155-T
Citations Scopus - 12
Show 158 more journal articles

Conference (12 outputs)

Year Citation Altmetrics Link
2017 Simpson JL, Pabreja K, Baines KJ, Eyres F, Yang M, Nair P, et al., 'Sputum Il-27 Gene Expression In Asthma Endotypes', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Washington, DC (2017)
Co-authors Katherine Baines, Jodie Simpson, Peter Gibson
2017 Tay HL, Hsu A, Nguyen T, Donovan C, Collison A, Mattes J, et al., 'Interleukin-36 gamma: Roles in lungs innate immunity, inflammation and allergy', CYTOKINE, Int Cytokine & Interferon Soc, Kanazawa, JAPAN (2017)
Co-authors Paul Foster, Joerg Mattes, Hock Tay, Philip Hansbro, Gerard Kaiko, Chantal Donovan, Alan Hsu, Adam Collison
2017 Pabreja K, Gibson PG, Baines KJ, Eyers F, Yang M, Nair P, et al., 'INCREASED EXPRESSION OF IL-27 IN NEUTROPHILIC ASTHMA', RESPIROLOGY (2017)
Co-authors Paul Foster, Katherine Baines, Peter Gibson, Jodie Simpson
2017 Nguyen TH, Maltby S, Simpson JL, Eyers F, Baines KJ, Gibson PG, et al., 'MACROPHAGES REGULATE THE DEVELOPMENT OF RSV INDUCED ASTHMA EXACERBATIONS', RESPIROLOGY (2017)
Co-authors Jodie Simpson, Steven Maltby, Katherine Baines, Paul Foster, Peter Gibson
2016 Hadjigol S, Maltby S, Yang M, Foster P, 'UNDERSTANDING MECHANISMS OF BACTERIAL-INDUCED DISEASE EXACERBATION IN A MOUSE MODEL OF ALLERGIC AIRWAYS DISEASE', RESPIROLOGY (2016)
Co-authors Paul Foster, Steven Maltby
2016 Tay H, Yang M, Hsu A, Nguyen T-H, Plank M, Maltby S, et al., 'Role of interleukin-36 gamma in regulating lung inflammation', EUROPEAN JOURNAL OF IMMUNOLOGY, Melbourne, AUSTRALIA (2016)
Co-authors Nathan Bartlett, Philip Hansbro, Alan Hsu, Steven Maltby
2016 Nguyen TH, Maltby S, Simpson JL, Eyers F, Gibson PG, Foster PS, Yang M, 'Macrophages regulate steroid resistant airway inflammation in a mouse model of respiratory syncytial virus-induced asthma exacerbation', EUROPEAN JOURNAL OF IMMUNOLOGY, Melbourne, AUSTRALIA (2016)
Co-authors Paul Foster, Jodie Simpson, Peter Gibson, Steven Maltby
2015 Tay H, Kaiko G, Plank M, Li J, Essilfie A, Maltby S, et al., 'THE ROLE OF MIR-328 IN RESPIRATORY DISEASES', RESPIROLOGY, Queensland, AUSTRALIA (2015) [E3]
Co-authors Philip Hansbro, Gerard Kaiko, Joerg Mattes, Paul Foster, Steven Maltby
2013 Hansbro P, Beckett E, Stevens R, Jarnicki A, Kim R, Hanish I, et al., 'A short-term model of COPD identifies a role for mast cell tryptase', JOURNAL OF IMMUNOLOGY, Honolulu, HI (2013) [E3]
Co-authors Philip Hansbro, Simon Keely, Jay Horvat, Nicole Hansbro, Peter Wark, Paul Foster, Emma Beckett
2012 Li J, Foster PS, Yang M, 'Inducible microRNA-X expression underpins steroid- resistant airway hyperresponsiveness by upregulating IL-27 expression', Respirology, Canberra, ACT (2012) [E3]
Co-authors Paul Foster
2011 Foster P, Li J, Wang W, Baines K, Bowden N, Hansbro P, et al., 'IL-27 underpins steroid resistant airway hyperresponsiveness via MyD88 dependent pathways', ALLERGY, Istanbul, TURKEY (2011) [E3]
Co-authors Nikola Bowden, Philip Hansbro, Peter Gibson
2008 Yang M, Ma C, Foster PS, 'Antigen-specific TH1 cells induce airway hyper-reactivity in co-operation with lipopolysaccharide in BALB/C mice', Respirology, Melbourne, VIC (2008) [E3]
DOI 10.1111/j.1440-1843.2008.01252.x
Co-authors Paul Foster
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Grants and Funding

Summary

Number of grants 21
Total funding $5,442,437

Click on a grant title below to expand the full details for that specific grant.


20171 grants / $830,053

Shared innate immune mechanisms underpin-steroid resistant pathogen-induced asthma exacerbations$830,053

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Paul Foster, Doctor Ming Yang, Associate Professor Nathan Bartlett
Scheme Project Grant
Role Investigator
Funding Start 2017
Funding Finish 2020
GNo G1600084
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

20152 grants / $22,000

Blocking the negative effects of stress on the brain to promote better healing of the brain after stroke$20,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Associate Professor Rohan Walker, Doctor Lin Kooi Ong, Doctor Ming Yang, Professor Sarah Johnson
Scheme Project Grant
Role Investigator
Funding Start 2015
Funding Finish 2015
GNo G1501384
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

9th Biennial Symposium of the International Esoinophil Society, Chicago USA, 14-18 July 2015$2,000

Funding body: University of Newcastle - Faculty of Health and Medicine

Funding body University of Newcastle - Faculty of Health and Medicine
Project Team Doctor Ming Yang
Scheme Travel Grant
Role Lead
Funding Start 2015
Funding Finish 2015
GNo G1500734
Type Of Funding Internal
Category INTE
UON Y

20141 grants / $700,623

New way of treating respiratory infections and airway inflammatory diseases by targeting miRNA $700,623

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Paul Foster, Doctor Ming Yang
Scheme Project Grant
Role Investigator
Funding Start 2014
Funding Finish 2016
GNo G1300121
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

20131 grants / $20,000

DP73 Digital colour and monochrome camera + cellSens software + Xcite120 fluorescence lamp illuminator$20,000

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Paul Foster, Doctor Alan Hsu, Professor Phil Hansbro, Professor Joerg Mattes, Doctor Katie Baines, Professor Jodie Simpson, Professor Rakesh Kumar, Doctor Nicole Hansbro, Doctor Steven Maltby, Doctor Ming Yang, Doctor Gerard Kaiko, Associate Professor Jay Horvat, Associate Professor Simon Keely, Doctor Andrew Jarnicki, Doctor Michael Fricker
Scheme Equipment Grant
Role Investigator
Funding Start 2013
Funding Finish 2013
GNo G1201186
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

20122 grants / $564,551

Understanding the mechanisms of steroid resistant inflammatory pathways in mouse models of asthma: potential new treatment approaches$514,551

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Paul Foster, Doctor Ming Yang
Scheme Project Grant
Role Investigator
Funding Start 2012
Funding Finish 2014
GNo G1100099
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

SpectraMax M5e Multi-Mode Microplate Reader$50,000

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Paul Foster, Professor Phil Hansbro, Professor Joerg Mattes, Professor Rakesh Kumar, Doctor Nicole Hansbro, Doctor Ming Yang, Associate Professor Jay Horvat, Associate Professor Simon Keely, Doctor Andrew Jarnicki, Doctor Linda Howland, Doctor Kelly Asquith
Scheme Equipment Grant
Role Investigator
Funding Start 2012
Funding Finish 2012
GNo G1100975
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

20113 grants / $429,250

Targeting pro-survival mechanisms to sensitize human melanoma to immunotherapy$359,250

Funding body: Cancer Council NSW

Funding body Cancer Council NSW
Project Team Professor Xu Dong Zhang, Doctor Ming Yang
Scheme Research Program
Role Investigator
Funding Start 2011
Funding Finish 2013
GNo G1000379
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

SCIREQ FlexiVentFX system + FlexiVentFX extension$45,000

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Professor Phil Hansbro, Laureate Professor Paul Foster, Professor Joerg Mattes, Associate Professor Simon Keely, Associate Professor Jay Horvat, Doctor Nicole Hansbro, Doctor Ming Yang, Doctor Catherine Ptaschinski, Doctor Kelly Asquith, Doctor Gough Au, Conjoint Professor Peter Wark, Laureate Professor John Aitken, Conjoint Professor Keith Jones, Laureate Professor Roger Smith, Professor Judith Black, Professor Rakesh Kumar, Professor Paul Hertzog
Scheme Equipment Grant
Role Investigator
Funding Start 2011
Funding Finish 2011
GNo G1100037
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

Targeting Pro-Survival Mechanisms to Sensitize Human Melanoma to Immunotherapy$25,000

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Professor Xu Dong Zhang, Doctor Ming Yang
Scheme Near Miss Grant
Role Investigator
Funding Start 2011
Funding Finish 2011
GNo G1001046
Type Of Funding Internal
Category INTE
UON Y

20102 grants / $40,509

Buxco FinePointe software and FinePointe RC system for mice $39,000

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Paul Foster, Professor Phil Hansbro, Professor Joerg Mattes, Doctor Nicole Hansbro, Doctor Simon Phipps, Doctor Ming Yang, Doctor Kelly Asquith, Doctor Catherine Ptaschinski, Professor Rakesh Kumar, Professor Judith Black
Scheme Equipment Grant
Role Investigator
Funding Start 2010
Funding Finish 2010
GNo G1000053
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

40th Annual Scientific Meting for Australiasian Society for Immunology 2010, Perth, 5 - 9 December 2010$1,509

Funding body: University of Newcastle - Faculty of Health and Medicine

Funding body University of Newcastle - Faculty of Health and Medicine
Project Team Doctor Ming Yang
Scheme Travel Grant
Role Lead
Funding Start 2010
Funding Finish 2011
GNo G1001004
Type Of Funding Internal
Category INTE
UON Y

20091 grants / $41,150

Coulter counter$41,150

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Paul Foster, Professor Phil Hansbro, Professor Joerg Mattes, Doctor Simon Phipps, Doctor Ming Yang, Doctor Nicole Hansbro, Doctor Kelly Asquith
Scheme Equipment Grant
Role Investigator
Funding Start 2009
Funding Finish 2009
GNo G0189851
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

20084 grants / $564,200

Innate immune factors regulate steroid-resistant airways hyperreactivity and asthma$503,250

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Doctor Ming Yang
Scheme Project Grant
Role Lead
Funding Start 2008
Funding Finish 2010
GNo G0187617
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

Individually ventilated cages (IVC) and associated ventilator, holding boxes and water bottles$35,000

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Paul Foster, Professor Phil Hansbro, Professor Joerg Mattes, Doctor Simon Phipps, Doctor Ming Yang, Doctor Nicole Hansbro, Doctor Kelly Asquith
Scheme Equipment Grant
Role Investigator
Funding Start 2008
Funding Finish 2008
GNo G0188541
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

MicroRNA and antagomirs in the regulation and suppression of interferon (IFN)-g and lipopolysaccharide (LPS) induced steroid-resistant airways hyperreactivity$24,250

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Ming Yang, Laureate Professor Paul Foster
Scheme Project Grant
Role Lead
Funding Start 2008
Funding Finish 2008
GNo G0188474
Type Of Funding Contract - Aust Non Government
Category 3AFC
UON Y

The Thoracic Society of Australia and New Zealand Annual Scientific Meeting, Melbourne Australia, 30/3/2008 - 2/4/2008$1,700

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Doctor Ming Yang
Scheme Travel Grant
Role Lead
Funding Start 2008
Funding Finish 2008
GNo G0188618
Type Of Funding Internal
Category INTE
UON Y

20061 grants / $1,500

15th World Congress of pharmacology july 2-7, 2006$1,500

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Doctor Ming Yang
Scheme Travel Grant
Role Lead
Funding Start 2006
Funding Finish 2006
GNo G0186492
Type Of Funding Internal
Category INTE
UON Y

20053 grants / $2,228,601

Drug targets from new animal models$2,030,948

Funding body: CRC for Asthma

Funding body CRC for Asthma
Project Team Laureate Professor Paul Foster, Professor Phil Hansbro, Professor Joerg Mattes, Doctor Ming Yang, Dr Simon Phipps
Scheme Research Grant
Role Investigator
Funding Start 2005
Funding Finish 2011
GNo G0185860
Type Of Funding CRC - Cooperative Research Centre
Category 4CRC
UON Y

Understanding the role of IL-13 in the pathogenesis of asthma$168,173

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Doctor Ming Yang
Scheme Postdoctoral Research Fellowship
Role Lead
Funding Start 2005
Funding Finish 2007
GNo G0184063
Type Of Funding Internal
Category INTE
UON Y

Investigating the role of IL-13 induced arginas I activity in the development of allergic lung disease$29,480

Funding body: Ramaciotti Foundations

Funding body Ramaciotti Foundations
Project Team Doctor Ming Yang
Scheme Major Equipment Award
Role Lead
Funding Start 2005
Funding Finish 2005
GNo G0185636
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y
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Research Supervision

Number of supervisions

Completed3
Current2

Current Supervision

Commenced Level of Study Research Title Program Supervisor Type
2017 PhD Understanding the role of non-coding RNAs in the exacerbation of allergic airways disease PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2017 PhD Innate Type 2 Responses and Viral-Induced Asthma Exacerbation PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor

Past Supervision

Year Level of Study Research Title Program Supervisor Type
2017 PhD Modeling of Respiratory Syncytial Virus-induced Exacerbation of Allergic Airways Disease PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2017 PhD Understanding the Mechanisms of Bacterial-Induced Exacerbation of Allergic Airways Disease in a Mouse Model PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2014 PhD Respiratory Innate Immune Factors Regulate Steroid-resistant Airway Hyperreactivity and Asthma PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
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Dr Ming Yang

Position

Senior Lecturer
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine

Focus area

Immunology and Microbiology

Contact Details

Email ming.yang@newcastle.edu.au
Phone (02) 40420183

Office

Room Level 2, Immunology & Microbiology
Building HMRI Building
Location HMRI Building

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