Circ_0005615 contributes to the progression and Bortezomib resistance of multiple myeloma by sponging miR-185-5p and upregulating IRF4

Abstract

Circular RNAs (circRNAs) have been shown to play critical regulatory roles in multiple myeloma progression. Here, we aimed to explore the biologic role of circ_0005615 in multiple myeloma progression and its associated mechanism. Cell counting kit-8 assay was conducted to analyze the bortezomib resistance and proliferation of multiple myeloma cells. Cell proliferation was also analyzed by 5-Ethynyl-2'-deoxyuridine incorporation and flow cytometry assays. Cell apoptosis was assessed by flow cytometry. The interaction between microRNA-185-5p (miR-185-5p) and circ_0005615 or interferon regulatory factor 4 (IRF4) was verified by the dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. A xenograft tumor model was established in non-obese diabetic/server combined immune-deficiency mice to analyze the roles of circ_0005615 in tumor growth and bortezomib resistance. Circ_0005615 was upregulated in multiple myeloma tissues and cell lines. Circ_0005615 knockdown restrained the bortezomib resistance and proliferation and induced the apoptosis of multiple myeloma cells. Circ_0005615 acted as a molecular sponge for miR-185-5p, and the antitumor effects mediated by circ_0005615 knockdown were reversed by silencing miR-185-5p. IRF4 was confirmed as a direct target of miR-185-5p, and miR-185-5p overexpression-induced antitumor influences could be counteracted by IRF4 overexpression. Circ_0005615 could positively regulate IRF4 expression by sponging miR-185-5p in multiple myeloma cells. Circ_0005615 knockdown suppressed the growth and bortezomib resistance of xenograft tumors in vivo. Circ_0005615 contributed to the malignant progression and bortezomib resistance of multiple myeloma through mediating miR-185-5p/IRF4 signaling.