Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair.
Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair.
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Let-7e通过抑制DNA双链断裂修复使上皮性卵巢癌对顺铂敏感
DOI：
10.1186/s13048-017-0321-8
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发表时间：
2017-04-04
影响因子：
4
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Xiao M;Cai J;Cai L;Jia J;Xie L;Zhu Y;Huang B;Jin D;Wang Z
背景对铂类化疗药物的耐药仍然是卵巢癌治疗的一大挑战。人类let-7家族包含位于9条不同染色体上的13个成员，大多数成员与癌症药物敏感性的调节有关。我们以前的研究表明，let-7 e在上皮性卵巢癌（EOC）中的失调促进了顺铂耐药的发展。在本研究中，我们的目的是探讨潜在的机制，并进一步评估的临床价值，让-7 e在预测化学反应和预后在EOC.ResultsIn原位杂交分析显示，让-7 e的表达显着降低化疗耐药EOC组织相比，化学敏感的情况下。转染let-7 e agomir可使EOC细胞对顺铂敏感，下调BRCA 1和Rad 51的表达，抑制顺铂诱导的DNA双链断裂修复，而let-7 e抑制剂则具有相反的作用。在人卵巢癌组织中，BRCA 1和Rad 51水平在化疗耐药组中比敏感组升高，并且与let-7 e呈负相关。低let-7 e和高Rad 51与不良无进展生存期和总生存期显著相关，多变量回归分析显示let-7 e是EOC患者总生存期和化疗反应的独立预测因子。受试者工作特征分析显示let-7 e水平对铂类紫杉类化疗耐药具有高度预测性，曲线下面积为0.826。结论在卵巢癌中，let-7 e水平降低导致BRCA 1和Rad 51表达激活，DSB修复增强，从而导致顺铂耐药。Let-7 e是EOC生存和化疗反应的潜在预测因子，let-7 e的再表达可能是克服化疗耐药的有效策略。
BackgroundResistance to platinum-based chemotherapy remains a great challenge for ovarian cancer treatment. The human let-7 family contains 13 members located on nine different chromosomes, and most members have been implicated in the modulation of drug sensitivity in cancers. Our previous study showed that deregulation of let-7e in epithelial ovarian cancer (EOC) promoted the development of resistance to cisplatin. In the present study, we aimed to investigate the underlying mechanism and further evaluate the clinical value of let-7e in predicting chemo-response and prognosis in EOC.ResultsIn situ hybridization assays revealed a significantly decreased expression of let-7e in chemo-resistant EOC tissues compared with chemo-sensitive cases. Transfection with let-7e agomir sensitized EOC cells to cisplatin, down-regulated BRCA1 and Rad51 expression, and repressed the repair of cisplatin-induced DNA double strand break, while let-7e inhibitor exerted the opposite effects. In human EOC tissues, BRCA1 and Rad51 levels were increased in the chemo-resistant group compared with the sensitive group and were negatively correlated with let-7e. Low let-7e and high Rad51 were significantly associated with poor progression-free survival and overall survival and multivariate regression analyses showed that let-7e was an independent predictor for overall survival and chemotherapy response in EOC. Receiver operating characteristic analysis indicated that let-7e level was highly predictive of resistance to platinum-taxane chemotherapy with an area under the curve of 0.826.ConclusionsIn EOC, low let-7e leads to activation of BRCA1 and Rad51 expression and subsequent enhancement of DSB repair, which in turn results in cisplatin-resistance. Let-7e is a potential predictor for survival and chemo-response in EOC and re-expression of let-7e might be an effective strategy for overcoming chemo-resistance.