Abstract
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.
Highlights
MLH1 plays a critical role in maintaining the fidelity of DNA replication, and defects in human MLH1 have been reported
We investigated the role of MLH1 in the sensitivity of human endometrial carcinoma cells to cisplatin and generated an adenovirus vector (ADV) ADV-MLH1 that can be widely applied for selective overexpression of MLH1, which represents a potential therapeutic target for endometrial carcinoma
Mismatch recognition is performed by MutSα, which is composed of MSH2 and MSH6, and MutSβ (MSH2-MSH3), whereas the recruitment of downstream mismatch repair (MMR) proteins is executed by MutLα, which is composed of MLH1-PMS2 [21]
Summary
MLH1 plays a critical role in maintaining the fidelity of DNA replication, and defects in human MLH1 have been reported. The role of MLH1 in endometrial carcinoma has not been fully investigated. We aimed to study the role of MLH1 in the sensitivity of human endometrial carcinoma cells to cisplatin. Women with hereditary nonpolyposis colorectal cancer exhibit a 40 to 60% cumulative lifetime risk for endometrial carcinoma, which arises as a result of a genetic predisposition to the disease, characterized by mutations in DNA mismatch repair (MMR) genes such as MLH1 and MSH2 [1]. Various models have demonstrated drug resistance caused by low levels of the MLH1 protein in ovarian and esophageal tumor samples following cisplatin (cis-dichlorodiammine platinum, CDDP)-based chemotherapy. Several studies, which examined MMR protein levels and microsatellite instability in germ cell
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