Metapristone (RU486-derivative) inhibits endometrial cancer cell progress through regulating miR-492/Klf5/Nrf1 axis

Abstract

Background: Endometrial cancer is the prevalent invasive gynecological cancer in the world. The pathogenesis of endometrial cancer involves many signaling pathways which are related with oestrogen, tumor-suppressor gene (e.g. PTEN) or microRNAs (e.g. miR-23a and miR-29b). Metapristone is a hormone-related drug and widely used in endometrial cancer clinical therapeutics. However, the deep regulatory mechanism of metapristone to endometrial cancer is not clear, especially the relationship with microRNAs. In this research, we aimed to figure out the specific molecular mechanism on the regulation of metapristone to microRNAs during the treatment of endometrial cancer.Methods: RL95-2 cells and Ishikawa cells were used as the endometrial cancer cell models. MiR-492 or si-miR-492 was transfected into RL95-2 cells and Ishikawa cells to explore the role of miR-492 in endometrial cancer. Moreover, the mice tumor model was used to confirm the function of metapristone and the regulating process by miR-492/Klf5/Nrf1 axis in vivo. Mechanically, cell proliferation was monitored using the MTT assay, cell colony formation assay and EdU assay. Luciferase reporter assay was used to identify the downstream target gene of miR492. The protein expression and RNA expression were respectively measured by western blot and qRT-PCR for cell signaling pathway research, subsequently, were verified in the mice tumor model via immunohistochemistry.Results: Metapristone as a kind of hormone-related drugs significantly inhibited the endometrial cancer cell growth through regulating cell apoptosis-related gene expression. Mechanically, miR-492 and its target genes Klf5 and Nrf1 were highly expressed in the endometrial cancer cell lines, which promoted cell proliferation and inhibited cell apoptosis. Metapristone decreased the expression of miR-492 and its target genes Klf5 and Nrf1, leading to endometrial cancer cell growth inhibition in vitro and in vivo.Conclusion: Metapristone inhibited the endometrial cancer cell growth through regulating the cell apoptosis-related signaling pathway and inhibiting the expression of miR-492 and its downstream target genes (Klf5 and Nrf1), which provided the theoretical basis of endometrial cancer in clinical treatment.