Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells
Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells
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DOI：
10.1073/pnas.1421365112
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发表时间：
2015-04-07
影响因子：
11.1
通讯作者：
Wang, Qi-En
中科院分区：
文献类型：
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作者：
Srivastava, Amit Kumar;Han, Chunhua;Wang, Qi-En
具有增强的致瘤性和化学抗性的癌症干细胞（CSC）被认为是卵巢癌患者中治疗失败和肿瘤复发的原因。然而，目前尚不清楚CSC如何在DNA损伤剂处理后存活。在这里，我们报告了从卵巢癌细胞系和原发性肿瘤中分离的卵巢CSC中DNA聚合酶eta（Pol eta）的表达升高，表明CSC可能具有内在增强的跨病变DNA合成（TLS）。Pol eta的下调通过增强顺铂诱导的CSC细胞凋亡在体外和体内阻断顺铂诱导的CSC富集，表明Pol eta介导的TLS有助于顺铂治疗后CSC的存活。此外，我们的数据证明了卵巢CSC中miR-93的耗尽。卵巢CSC中miR-93的增强表达降低了Pol.表达并增加了其对顺铂的敏感性。综上所述，我们的数据表明，卵巢CSC具有内在增强的Poleta介导的TLS，允许CSC在顺铂治疗中存活，导致肿瘤复发。靶向Pol eta，可能通过增强miR-93的表达，可能被开发作为一种策略，以增加顺铂治疗的疗效。
Cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance are believed to be responsible for treatment failure and tumor relapse in ovarian cancer patients. However, it is still unclear how CSCs survive DNA-damaging agent treatment. Here, we report an elevated expression of DNA polymerase eta(Pol eta) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically enhanced translesion DNA synthesis (TLS). Down-regulation of Pol eta blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol eta-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol. expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically enhanced Pol eta-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol eta, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.