Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer
Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer
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DOI：
10.1136/gutjnl-2011-301113
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发表时间：
2013-01-01
期刊：
影响因子：
24.5
通讯作者：
Tan, Patrick
中科院分区：
文献类型：
--
作者：
Ivanova, Tatiana;Zouridis, Hermioni;Tan, Patrick
目的顺铂是一种应用广泛的胃癌化疗药物，但调控胃癌对顺铂疗效的遗传因素尚不清楚。识别调控顺铂耐药性的基因可以帮助临床医生定制治疗方案，将顺铂敏感患者与可能受益于替代铂疗法的患者区分开来，并突出克服顺铂耐药的新的靶向策略。设计20株胃癌细胞株，进行基因表达谱、DNA甲基化谱和药物反应分析。整合分子数据以确定在顺铂耐药株系中高表达和未甲基化的基因。通过几种体外和体内测试对候选基因进行了功能测试。结果表观基因组分析证实骨形态发生蛋白4(BMP4)是顺铂耐药株中高表达的表观遗传调控基因。功能分析证实，BMP4对于一些原癌性状的表达是必要和充分的，可能是通过刺激上皮-间充质转化来调节的。在原发肿瘤中，BMP4启动子甲基化水平与BMP4表达呈负相关，BMP4高表达肿瘤患者的预后明显较差。在治疗方面，靶向的BMP4基因抑制导致GC细胞对顺铂显著增敏。值得注意的是，表达BMP4的GC对奥沙利铂也没有交叉耐药。结论BMP4的表观遗传和表达状态可能是GC顺铂耐药的潜在生物标志物。靶向BMP4可能会使GC细胞对顺铂敏感。奥沙利铂是临床上可接受的顺铂替代品，可能代表着BMP4阳性GCs的潜在治疗选择。
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.