hMSH2 Coordinated with the Expression of E2F1 Promotes Platinum Response in Epithelial Ovarian Cancer

Abstract

Abstract Purpose Previous studies have demonstrated that hMSH2 deficiency decreased platinum response in EOC. This study is to explore the underlying mechanism that regulates hMSH2 expression and drug susceptibility. Methods Transcription factors (TFs) that potentially regulate hMSH2 were predicted by bioinformatics analysis. RT-qPCR, Western blot, and luciferase assay were carried out in ovarian cancer cell lines to verify the identified TF. Expressions of the identified TF were modulated via overexpression or knockdown, and the corresponding cellular responses to the cisplatin were examined. Kaplan-Meier analysis was used to verify the correlation between the identified TF and EOC patients’ clinical outcomes. Results The common transcription factor E2F1 was identified to bind the promoter region of the hMSH2 gene and presented a positive correlation with the expression of hMSH2 in the public database. RT-PCR and Western blot verified the coordinate expression of E2F1 and hMSH2 in ovarian cancer cells. The luciferase assay also validated the regulation of hMSH2 by E2F1. The expression level of E2F1 is also found to correlate with cisplatin susceptibility in vitro. The Kaplan-Meier analyses of 77 EOC patients showed that low E2F1 expression was associated with worse survival. Conclusion E2F1 regulated MSH2 expression could play a vital role in the drug resistance of platinum-based treatments for ovarian cancer patients. The complex role of E2F1 in various cancers still needs to be further explored.