EIF4A3-induced circWAC promotes breast cancer progression through mediating miR-599/E2F3 axis.

Abstract

Circular RNAs (circRNAs) are implicated in the regulation of tumor progression via the "competitive endogenous RNAs (ceRNAs)" mechanism. We intended to explore the molecular mechanism of circRNA WW domain containing adaptor with coiled-coil (circWAC) in breast cancer (BC) progression. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were applied to analyze RNA and protein expression. Cell proliferation, migration, invasion, apoptosis, glycolysis, and tumorigenesis in nude mice were assessed to analyze the role of circWAC/microRNA-599 (miR-599)/E2F transcription factor 3 (E2F3) axis in BC. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA-pull down assay were performed to verify intermolecular interactions. CircWAC was up-regulated in BC tissues and cell lines. CircWAC knockdown restrained the proliferation, migration, invasion, and glycolysis and promoted the apoptosis of BC cells. CircWAC acted as miR-599 sponge, and miR-599 interference largely reversed circWAC silencing-induced effects in BC cells. MiR-599 interacted with the 3' untranslated region (3'UTR) of E2F3, and miR-599 overexpression-induced suppressive effect on cellular malignant potential was overturned by the accumulation of E2F3 in BC cells. Eukaryotic initiation factor 4A3 (eIF4A3) induced the expression of circWAC in BC cells. CircWAC knockdown suppressed xenograft tumor growth in vivo. Our results demonstrated that eIF4A3-induced circWAC promoted the proliferation, migration, invasion, and glycolysis and suppressed the apoptosis of BC cells through mediating miR-599/E2F3 axis, which provided novel potential targets for BC therapy.