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Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer

Authors
 Tatiana Ivanova  ;  Hermioni Zouridis  ;  Yonghui Wu  ;  Lai Ling Cheng  ;  Iain Beehuat Tan  ;  Veena Gopalakrishnan  ;  Chia Huey Ooi  ;  Julian Lee  ;  Luo Qin  ;  Jeanie Wu  ;  Minghui Lee  ;  Sun Young Rha  ;  Dan Huang  ;  Natalia Liem  ;  Khay Guan Yeoh  ;  Wei Peng Yong  ;  Bin Tean Teh  ;  Patrick Tan 
Citation
 Gut, Vol.62 : 22-33, 2013 
Journal Title
 Gut 
ISSN
 0017-5749 
Issue Date
2013
Abstract
OBJECTIVE: Cisplatin is a widely used gastric cancer (GC) chemotherapy; however, genetic factors regulating GC responses to cisplatin remain obscure. Identifying genes regulating cisplatin resistance could aid clinicians in tailoring treatments, by distinguishing cisplatin sensitive patients from those who might benefit from alternative platinum therapies, and highlight novel targeted strategies for overcoming cisplatin resistance. Here integrated epigenomics is applied to identify genes associated with GC cisplatin resistance. DESIGN: 20 GC cell lines were subjected to gene expression profiling, DNA methylation profiling and drug response assays. The molecular data were integrated to identify genes highly expressed and unmethylated specifically in cisplatin-resistant lines. Candidate genes were functionally tested by several in vitro and in vivo assays. Clinical impact of candidate genes was also assessed in a cohort of 197 GC patients. RESULTS: Epigenomic analysis identified bone morphogenetic protein 4 (BMP4) as an epigenetically regulated gene highly expressed in cisplatin-resistant lines. Functional assays confirmed that BMP4 is necessary and sufficient for the expression of several prooncogenic traits, likely mediated through stimulation of the epithelial-mesenchymal transition. In primary tumours, BMP4 promoter methylation levels were inversely correlated with BMP4 expression, and patients with high BMP4-expressing tumours exhibited significantly worse prognosis. Therapeutically, targeted genetic inhibition of BMP4 caused significant sensitisation of GC cells to cisplatin. Notably, BMP4-expressing GCs also did not exhibit cross resistance to oxaliplatin. CONCLUSIONS: BMP4 epigenetic and expression status may represent promising biomarkers for GC cisplatin resistance. Targeting BMP4 may sensitise GC cells to cisplatin. Oxaliplatin, a clinically acceptable cisplatin alternative, may represent a potential therapeutic option for BMP4-positive GCs.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/86582
DOI
10.1136/gutjnl-2011-301113
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
Yonsei Authors
라선영(Rha, Sun Young)
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Full Text
http://gut.bmj.com/content/62/1/22.long
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