miR-454 suppresses the proliferation and invasion of ovarian cancer by targeting E2F6

Abstract Background: It has been reported that hypoxia is closely related to the tumor malignancy and recurrence and regulates multiple hub genes in ovarian cancer. MicroRNA-454 (miR-454) has been confirmed to be involved in tumorigenesis and tumor development. However, the functional role of miR-454 in ovarian cancer remains unclear.Methods: The expression of miR-454 in ovarian cancer cells and serum of ovarian cancer patients was detected by RT-PCR. CCK8, colony formation, transwell, and flow cytometry assays were conducted to assess the effects of miR-454 on ovarian cancer cell proliferation, migration, invasion, and apoptosis. Dual-luciferase reporter assay was used to confirm the targeting relationship between miR-454 and E2F6. The expression pattern of E2F6 in ovarian cancer tissues was detected using immunohistochemistry assay. The relative expression of related proteins was examined using western blot analysis.Results: miR-454 was markedly down-regulated by hypoxia in ovarian cancer cells. Compared with normal serum, the expression of miR-454 was up-regulated in the serum of ovarian cancer patients, and was correlated with the clinicopathological stage of ovarian cancer patients. Next, we found that miR-454 overexpression inhibited the proliferation, migration and invasion of OVCAR3 and SKOV3 cells, as well as promoted apoptosis. In addition, the Akt/mTOR and Wnt/β-catenin signaling pathway were inhibited by miR-454. Bioinformatic analysis and dual-luciferase reporter assay confirmed that E2F6 was a target of miR-454 and negatively regulated by miR-454 in ovarian cancer cells. Moreover, immunohistochemical analysis showed that E2F6 was highly expressed in ovarian cancer tissues. Finally, we found that the increasing cell proliferation and migration triggered by E2F6 overexpression were abolished by miR-454 overexpression.Conclusion: Taken together, these results highlight the role of miR-454 as a tumor suppressor in ovarian cancer by targeting E2F6, indicating that the hypoxia/miR-454/E2F6 pathway may be a novel therapeutic approach for ovarian cancer.