生物
基因敲除
DNA甲基化
表观遗传学
癌变
癌症
基因
CDH1
癌症研究
表阿霉素
DNA损伤
遗传学
分子生物学
基因表达
DNA
细胞
乳腺癌
钙粘蛋白
作者
Jin Zhou,Wei Peng Yong,Chui Sun Yap,Aadhitthya Vijayaraghavan,Rohit A. Sinha,Brijesh Kumar Singh,Sam Xiu,Sravanthy Manesh,Anna Ngo,Andrea Lim,Carolyn Ang,Chen Xie,Foong Ying Wong,Suling J. Lin,Wei Keat Wan,Iain Beehuat Tan,Horst Flotow,Patrick Tan,Kiat‐Hon Lim,Paul M. Yen,Liang Kee Goh
出处
期刊:Carcinogenesis
[Oxford University Press]
日期:2015-03-05
卷期号:36 (4): 441-451
被引量:18
标识
DOI:10.1093/carcin/bgv014
摘要
Gastric cancer (GC) is the second leading cause of global cancer mortality worldwide. However, the molecular mechanism underlying its carcinogenesis and drug resistance is not well understood. To identify novel functionally important genes that were differentially expressed due to combinations of genetic and epigenetic changes, we analyzed datasets containing genome-wide mRNA expression, DNA copy number alterations and DNA methylation status from 154 primary GC samples and 47 matched non-neoplastic mucosa tissues from Asian patients. We used concepts of 'within' and 'between' statistical analysis to compare the difference between tumors and controls within each platform, and assessed the correlations between platforms. This 'multi-regulated gene (MRG)' analysis identified 126 differentially expressed genes that underwent a combination of copy number and DNA methylation changes. Most genes were located at genomic loci associated with GC. Statistical enrichment analysis showed that MRGs were enriched for cancer, GC and drug response. We analysed several MRGs that previously had not been associated with GC. Knockdown of DDX27, TH1L or IDH3G sensitized cells to epirubicin or cisplatin, and knockdown of RAI14 reduced cell proliferation. Further studies showed that overexpression of DDX27 reduced epirubicin-induced DNA damage and apoptosis. Levels of DDX27 mRNA and protein were increased in early-stage gastric tumors, and may be a potential diagnostic and prognostic marker for GC. In summary, we used an integrative bioinformatics strategy to identify novel genes that are altered in GC and regulate resistance of GC cells to drugs in vitro.
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