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MiR-34c Targets MET to Improve the Anti-Tumor Effect of Cisplatin on Ovarian Cancer.

ABSTRACT: Background:Cisplatin is a commonly used drug for the treatment of various types of malignant cancers, including ovarian cancer. However, resistance to cisplatin is still a considerable obstacle to achieve a satisfactory therapeutic effect. The purpose of this study is to develop a strategy to sensitize ovarian cancer cells to cisplatin-induced cytotoxicity. Methods:miR-34c levels in ovarian cancer tissues and cell lines were tested by qRT-PCR analysis. In vitro assays, the effect of miR-34c on cisplatin was evaluated by using MTT. Expression of MET and phosphorylation of PI3K and AKT were tested by Western blot assays. Conjugation with Bad and Bcl-xl was evaluated through immunoprecipitation. Flow cytometry analysis was performed to measure the apoptotic rate of ovarian cancer cells. Results:Downregulation of miR-34c was observed in ovarian cancer tissues and cell lines. However, miR-34c overexpression was found to sensitize ovarian cancer cells to cisplatin treatment in vitro and in vivo. Mechanically, we found that miR-34c targeted the MET gene, thereby inhibiting the phosphorylation of PI3K and AKT to activate Bad. As a result, miR-34c reduced resistance of ovarian cancer cells to cisplatin-induced apoptosis. Conclusion:miR-34c/MET axis promotes cisplatin-induced cytotoxicity against ovarian cancer by targeting the MET/PI3K/AKT/Bad pathway.

SUBMITTER: Yang S

PROVIDER: S-EPMC7148417 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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miR-34c Targets MET to Improve the Anti-Tumor Effect of Cisplatin on Ovarian Cancer.

Yang Shiying S Li Zhen Z Luo Rui R

OncoTargets and therapy 20200405

<h4>Background</h4>Cisplatin is a commonly used drug for the treatment of various types of malignant cancers, including ovarian cancer. However, resistance to cisplatin is still a considerable obstacle to achieve a satisfactory therapeutic effect. The purpose of this study is to develop a strategy to sensitize ovarian cancer cells to cisplatin-induced cytotoxicity.<h4>Methods</h4>miR-34c levels in ovarian cancer tissues and cell lines were tested by qRT-PCR analysis. In vitro assays, the effect ...[more]

PMID: 32308421

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Project description:BackgroundAccumulating evidence has revealed that aberrant microRNA (miRNA) expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. Emerging evidence has demonstrated that miR-133a participates in the tumorigenesis of various cancers. However, whether miR-133a is associated with cisplatin resistance in ovarian cancer remains unclear.ObjectiveTo investigate the role of miR-133a in the development of cisplatin resistance in ovarian cancer.MethodsMiR-133a expression in cisplatin-resistant ovarian cancer cell lines was assessed by reverse-transcription quantitative PCR (RT-qPCR). A cell counting kit-8 (CCK-8) assay was used to evaluate the viability of tumour cells treated with cisplatin in the presence or absence of miR-133a. A luciferase reporter assay was used to analyse the binding of miR-133a with the 3' untranslated region (3'UTR) of YES proto-oncogene 1 (YES1). The YES1 expression level was analysed using a dataset from the International Cancer Genome Consortium (ICGC) and assessed by RT-qPCR and western blotting in vitro. The roles and mechanisms of YES1 in cell functions were further probed via gain- and loss-of-function analysis.ResultsThe expression of miR-133a was significantly decreased in cisplatin-resistant ovarian cancer cell lines (A2780-DDP and SKOV3-DDP), and the overexpression of the miR-133a mimic reduced cisplatin resistance in A2780-DDP and SKOV3-DDP cells. Treatment with the miR-133a inhibitor increased cisplatin sensitivity in normal A2780 and SKOV3 cells. MiR-133a binds the 3'UTR of YES1 and downregulates its expression. Bioinformatics analysis revealed that YES1 expression was upregulated in recurrent cisplatin-resistant ovarian cancer tissue, and in vitro experiments also verified its upregulation in cisplatin-resistant cell lines. Furthermore, we discovered that miR-133a downregulated the expression of YES1 and thus inhibited cell autophagy to reduce cisplatin resistance. Yes1 knockdown significantly suppressed the cisplatin resistance of ovarian cancer cells by inhibiting autophagy in vitro. Xenograft tumour implantation further demonstrated that Yes1 overexpression promoted ovarian tumour development and cisplatin resistance.ConclusionsOur results suggest that the miR-133a/YES1 axis plays a critical role in cisplatin resistance in human ovarian cancer by regulating cell autophagy, which might serve as a promising therapeutic target for ovarian cancer chemotherapy treatment in the future.

Dataset Information

MiR-34c Targets MET to Improve the Anti-Tumor Effect of Cisplatin on Ovarian Cancer.

Publications

miR-34c Targets MET to Improve the Anti-Tumor Effect of Cisplatin on Ovarian Cancer.

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