circCELSR1 facilitates ovarian cancer proliferation and metastasis by sponging miR-598 to activate BRD4 signals

Abstract

BACKGROUND: Ovarian cancer is one of the most common gynecologic cancers and has high mortality rate due to the lack of early diagnosis method and efficient therapeutic agents. circCELSR1 is up-regulated in ovarian cancer, but its role and mechanisms in ovarian cancer are unclear. METHODS: Gene expression of circCELSR1, miR-598 and BRD4 in ovarian cells was examined by qRT-PCR. Protein level was determined by Western blotting. Bioinformatic analysis and luciferase assay determined the molecular binding among circCELSR1, miR-598 and BRD4 3' UTR. Cell proliferation, migration, invasion and apoptosis were determined by colony formation, wound healing assay, transwell assay and flow cytometry analysis, respectively. An abdominal cavity metastasis nude mice model was used to determine the in vivo function of circCELSR1. RESULTS: circCELSR1 and BRD4 were promoted, but miR-598 was suppressed in various ovarian cancer cells. circCELSR1 bound to miR-598 and promoted expression of its downstream target BRD4. Knockdown of circCELSR1 suppressed proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), but promoted apoptosis in ovarian cancer cells, and these effects were reversed by miR-598 inhibition or BRD4 overexpression. circCELSR1 inhibition decreased the expression of BRD4 and its downstream proliferation/migration related genes by targeting miR-598. Furthermore, knockdown of circCELSR1 suppressed ovarian cancer growth and metastasis in nude mice. CONCLUSION: Knockdown of circCELSR1 inhibited BRD4-mediated proliferation/migration related signaling via sponging miR-598, thereby repressing ovarian cancer progression. This study provides a new regulatory mechanism of ovarian cancer may facilitate the development of therapeutic agents for ovarian cancer.