Duke-NUS Graduate Medical School, 11 Hospital Drive, Singapore 169610, Singapore.
Gut. 2013 Jan;62(1):22-33. doi: 10.1136/gutjnl-2011-301113. Epub 2012 Apr 25.
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.
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.
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.
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.
顺铂是一种广泛应用于胃癌（GC）的化疗药物；然而，调节 GC 对顺铂反应的遗传因素仍不清楚。鉴定调节顺铂耐药的基因可以帮助临床医生通过区分顺铂敏感的患者和可能受益于替代铂类治疗的患者，从而进行个体化治疗，并为克服顺铂耐药提供新的靶向策略。本研究应用整合表观基因组学来鉴定与 GC 顺铂耐药相关的基因。
对 20 株 GC 细胞系进行基因表达谱、DNA 甲基化谱和药物反应检测。整合分子数据，鉴定在顺铂耐药系中特异性高表达且低甲基化的基因。通过多种体外和体内实验对候选基因进行功能验证。还在 197 例 GC 患者队列中评估候选基因的临床意义。
表观基因组分析鉴定出骨形态发生蛋白 4（BMP4）是一种在顺铂耐药系中高表达的受表观调控的基因。功能实验证实，BMP4 是表达多种致癌表型的必需和充分条件，可能通过刺激上皮-间充质转化来介导。在原发性肿瘤中，BMP4 启动子甲基化水平与 BMP4 表达呈负相关，高表达 BMP4 的肿瘤患者预后明显较差。在治疗上，靶向抑制 BMP4 可显著增加 GC 细胞对顺铂的敏感性。值得注意的是，BMP4 表达的 GC 细胞也未表现出对奥沙利铂的交叉耐药性。
BMP4 的表观遗传学和表达状态可能是 GC 顺铂耐药的有前途的生物标志物。靶向 BMP4 可能使 GC 细胞对顺铂敏感。奥沙利铂是一种临床可接受的顺铂替代品，可能是 BMP4 阳性 GC 的潜在治疗选择。
