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首页> 外文期刊>BMC Medical Genomics >Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer
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Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer

机译：DNA甲基化和基因表达的综合分析揭示了与卵巢癌铂耐药相关的特定信号通路

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Background Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Although the precise mechanism(s) underlying the development of platinum resistance in late-stage ovarian cancer patients currently remains unknown, CpG-island (CGI) methylation, a phenomenon strongly associated with aberrant gene silencing and ovarian tumorigenesis, may contribute to this devastating condition. Methods To model the onset of drug resistance, and investigate DNA methylation and gene expression alterations associated with platinum resistance, we treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After several cycles of drug selection, the isogenic drug-sensitive and -resistant pairs were subjected to global CGI methylation and mRNA expression microarray analyses. To identify chemoresistance-associated, biological pathways likely impacted by DNA methylation, promoter CGI methylation and mRNA expression profiles were integrated and subjected to pathway enrichment analysis. Results Promoter CGI methylation revealed a positive association (Spearman correlation of 0.99) between the total number of hypermethylated CGIs and GI50 values ( i.e ., increased drug resistance) following successive cisplatin treatment cycles. In accord with that result, chemoresistance was reversible by DNA methylation inhibitors. Pathway enrichment analysis revealed hypermethylation-mediated repression of cell adhesion and tight junction pathways and hypomethylation-mediated activation of the cell growth-promoting pathways PI3K/Akt, TGF-beta, and cell cycle progression, which may contribute to the onset of chemoresistance in ovarian cancer cells. Conclusion Selective epigenetic disruption of distinct biological pathways was observed during development of platinum resistance in ovarian cancer. Integrated analysis of DNA methylation and gene expression may allow for the identification of new therapeutic targets and/or biomarkers prognostic of disease response. Finally, our results suggest that epigenetic therapies may facilitate the prevention or reversal of transcriptional repression responsible for chemoresistance and the restoration of sensitivity to platinum-based chemotherapeutics.
机译：背景信息顺铂和卡铂是治疗卵巢癌的主要一线治疗方法。然而，对这些基于铂的药物的抗药性在绝大多数最初反应的肿瘤中发生，导致完全的化学抗药性，致命性疾病。尽管目前尚不清楚晚期卵巢癌患者铂耐药性发展的确切机制，但CpG-岛（CGI）甲基化是一种与异常基因沉默和卵巢肿瘤发生密切相关的现象，可能会导致这种破坏性疾病。方法为了模拟耐药性的发作，并研究与铂耐药性相关的DNA甲基化和基因表达的变化，我们用浓度递增的顺铂处理了克隆衍生的药物敏感性A2780上皮性卵巢癌细胞。经过几个周期的药物选择后，对同基因的药物敏感性和耐药性对进行整体CGI甲基化和mRNA表达微阵列分析。为了鉴定与化学抗性相关的基因，可能受DNA甲基化影响的生物途径，启动子CGI甲基化和mRNA表达谱被整合，并进行了途径富集分析。结果启动子CGI甲基化显示，在连续的顺铂治疗周期后，高甲基化CGI总数与GI 50 值（即耐药性增加）之间呈正相关（Spearman相关性为0.99）。与该结果一致，DNA甲基化抑制剂可逆化学耐药性。途径富集分析揭示了高甲基化介导的细胞粘附和紧密连接途径的抑制以及低甲基化介导的细胞生长促进途径PI3K / Akt，TGF-β和细胞周期进程的激活，这可能有助于卵巢中化学抗性的发作癌细胞。结论在卵巢癌铂耐药性发生过程中观察到不同生物学途径的选择性表观遗传破坏。 DNA甲基化和基因表达的综合分析可以确定新的治疗靶标和/或预后疾病反应的生物标志物。最后，我们的结果表明，表观遗传疗法可能有助于预防或逆转负责化学抗性的转录抑制，并恢复对铂基化学疗法的敏感性。

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