MLH1 enhances the sensitivity of human endometrial carcinoma cells to cisplatin by activating the MLH1/c-Abl apoptosis signaling pathway
MLH1 enhances the sensitivity of human endometrial carcinoma cells to cisplatin by activating the MLH1/c-Abl apoptosis signaling pathway
复制标题
MLH1通过激活MLH1/c-Abl凋亡信号通路增强人子宫内膜癌细胞对顺铂的敏感性
DOI：
10.1186/s12885-018-5218-4
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发表时间：
2018-12-29
期刊：
影响因子：
3.8
通讯作者：
Yang, Xingsheng
中科院分区：
文献类型：
--
作者：
Li, Yue;Zhang, Shihong;Yang, Xingsheng
MLH1在维持DNA复制保真度方面起着至关重要的作用，已经报道了人类MLH1的缺陷。然而，MLH1在子宫内膜癌中的作用尚未得到充分研究。因此，我们旨在研究MLH1在人子宫内膜癌细胞对顺铂敏感性中的作用。方法本研究检测了MLH1在石川细胞和RL95-2细胞中的表达。MLH1的沉默和过表达分别采用MLH1- sirna和adva -MLH1。通过实时聚合酶链反应、Western blotting、细胞增殖实验、流式细胞术细胞周期和凋亡分析来探讨其潜在机制。采用小鼠异种移植模型研究顺铂治疗后MLH1对肿瘤生长的影响。结果石川细胞中MLH1的过表达可显著提高细胞对顺铂的敏感性，促进细胞凋亡。相比之下，在体外敲除MLH1产生相反的效果。机制上，顺铂诱导adv -MLH1感染的子宫内膜癌细胞MLH1/c-Abl凋亡信号通路，这些作用涉及c-Abl、caspase-9、caspase-3和PARP。总之，我们的研究结果表明，ADV-MLH1可能在体内减弱石川细胞的生长，导致顺铂敏感性增加。结论smlh1可能通过激活MLH1/c-Abl凋亡信号通路使子宫内膜癌细胞对顺铂更敏感。此外，我们还生成了一种适用于子宫内膜癌中MLH1过表达的腺病毒载体（adva -MLH1）。因此，ADV-MLH1可能是子宫内膜癌的一个新的潜在治疗靶点。
BackgroundMLH1 plays a critical role in maintaining the fidelity of DNA replication, and defects in human MLH1 have been reported. However, the role of MLH1 in endometrial carcinoma has not been fully investigated. Therefore, we aimed to study the role of MLH1 in the sensitivity of human endometrial carcinoma cells to cisplatin.MethodsIn this study, we detected the expression of MLH1 in Ishikawa and RL95–2 cells. MLH1-siRNA and ADV-MLH1 were adopted for the silencing and overexpression of MLH1, respectively. Real-time polymerase chain reaction, Western blotting, cell proliferation assays, and cell cycle and apoptotic analyses by flow cytometry were employed to explore the underlying mechanism. A mouse xenograft model was used to investigate the effect of MLH1 on tumor growth after treatment with cisplatin.ResultsOver-expression of MLH1 in Ishikawa cells dramatically increased the sensitivity of cells to cisplatin and enhanced cell apoptosis. By contrast, knockdown of MLH1 yielded the opposite effects in vitro. Mechanistically, cisplatin induced the MLH1/c-Abl apoptosis signaling pathway in ADV-MLH1-infected endometrial carcinoma cells, and these effects involved c-Abl, caspase-9, caspase-3 and PARP. Altogether, our results indicate that ADV-MLH1 might attenuate Ishikawa cell growth in vivo, resulting in increased cisplatin sensitivity.ConclusionsMLH1 may render endometrial carcinoma cells more sensitive to cisplatin by activating the MLH1/c-Abl apoptosis signaling pathway. In addition, an applicable adenovirus vector (ADV-MLH1) for MLH1 overexpression in endometrial carcinoma was generated. Thus, ADV-MLH1 might be a novel potential therapeutic target for endometrial carcinoma.