Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer.
Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer.
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DOI：
10.1016/j.celrep.2015.12.046
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发表时间：
2016-01-26
期刊：
影响因子：
8.8
通讯作者：
Chowdhury D
中科院分区：
文献类型：
--
作者：
Choi YE;Meghani K;Brault ME;Leclerc L;He YJ;Day TA;Elias KM;Drapkin R;Weinstock DM;Dao F;Shih KK;Matulonis U;Levine DA;Konstantinopoulos PA;Chowdhury D
由于同源重组（HR）的潜在缺陷，BRCA 1/2突变的高级别浆液性卵巢癌（HGSOC）对双链DNA断裂（DSB）诱导剂[即铂和聚（ADP-核糖）聚合酶抑制剂（PARPis）]表现出改善的结局和敏感性。然而，对铂和PARPis的耐药性是这些患者长期生存的重要障碍。虽然BRCA 1/2回复突变是一种临床验证的耐药机制，但它们占铂类耐药BRCA 1/2突变HGSOC的不到一半。我们发现了一种耐药机制，通过这种机制，microRNA，miR-622通过靶向Ku复合物和恢复HR介导的DSB修复，诱导BRCA 1突变型HGSOC对PARPis和铂的耐药性。在生理学上，miR-622与细胞周期中Ku表达呈负相关，抑制非同源末端连接并促进S期HR介导的DSB修复。重要的是，miR-622在BRCA 1缺陷型HGSOC中的高表达与铂类化疗后的不良结局相关，表明通过HR挽救的microRNA介导的耐药。
High-grade serous ovarian carcinomas (HGSOCs) with BRCA1/2 mutations exhibit improved outcome and sensitivity to double-strand DNA break (DSB)-inducing agents [i.e. platinum and Poly(ADP-ribose) polymerase inhibitors (PARPis)] due to an underlying defect in homologous recombination (HR). However, resistance to platinum and PARPis represents a significant barrier to the long-term survival of these patients. Although, BRCA1/2-reversion mutations are a clinically validated resistance mechanism, they account for less than half of platinum resistant BRCA1/2-mutated HGSOCs. We uncover a resistance mechanism by which a microRNA, miR-622 induces resistance to PARPis and platinum in BRCA1-mutant HGSOCs by targeting the Ku complex and restoring HR-mediated DSB repair., Physiologically, miR-622 inversely correlates with Ku expression during the cell cycle, suppressing non-homologous end joining and facilitating HR-mediated DSB repair in S-phase. Importantly, high expression of miR-622 in BRCA1-deficient HGSOCs is associated with worse outcome after platinum chemotherapy, indicating microRNA-mediated resistance through HR rescue.