Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer.
Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer.
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DOI：
10.1186/1755-8794-2-34
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发表时间：
2009-06-08
影响因子：
2.7
通讯作者：
Nephew KP
中科院分区：
文献类型：
--
作者：
Li M;Balch C;Montgomery JS;Jeong M;Chung JH;Yan P;Huang TH;Kim S;Nephew KP
顺铂和卡铂是治疗卵巢癌的主要一线药物。然而，对这些铂类药物的耐药性发生在绝大多数最初有反应的肿瘤中，导致完全耐药的致命疾病。尽管晚期卵巢癌患者铂耐药发生的确切机制(S)目前尚不清楚，但CpG岛(CGI)甲基化可能导致这种毁灭性的疾病，这种现象与基因沉默和卵巢肿瘤发生密切相关。为了建立耐药模型，并研究与铂耐药相关的DNA甲基化和基因表达变化，我们用增加顺铂浓度的方法处理克隆衍生的、药物敏感的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和耐药对进行全球CGI甲基化和mRNA表达微阵列分析。为了识别与化疗耐药相关的、可能受DNA甲基化影响的生物途径，我们整合了启动子CGI甲基化和mRNA表达谱，并进行了途径富集化分析。启动子CGI甲基化显示，在顺铂连续治疗周期后，高甲基化CGI总数与GI50值(即耐药性增加)之间存在正相关(Spearman相关系数为0.99)。与此结果一致，化疗耐药可被DNA甲基化抑制剂逆转。途径丰富分析显示，高甲基化抑制细胞黏附和紧密连接通路，低甲基化介导细胞生长促进通路PI3K/Akt、转化生长因子-β和细胞周期进程的激活，这可能是卵巢癌细胞发生化疗耐药的原因之一。在卵巢癌铂耐药的发展过程中，观察到不同生物通路的选择性表观遗传学中断。DNA甲基化和基因表达的综合分析可能允许识别新的治疗靶点和/或预测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导致化疗耐药的转录抑制，并恢复对铂类化疗药物的敏感性。
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. 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. 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. 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.
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影响因子：
5.7
作者：
Balch, C;Yan, P;Nephew, KP
通讯作者：
Nephew, KP
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
8
作者：
Ehrlich, M;Woods, CB;Laird, PW
通讯作者：
Laird, PW
影响因子：
7
作者：
Draghici, Sorin;Khatri, Purvesh;Romero, Roberto
通讯作者：
Romero, Roberto
影响因子：
20.3
作者：
Chen, Gang;Ghosh, Paritosh;Longo, Dan L.
通讯作者：
Longo, Dan L.