Hsa_circ_0111738 Inhibits Tumor Progression and Angiogenesis in Multiple Myeloma by Sponging miR-1233-3p to Regulate HIF-1 Signaling Pathway

Abstract

Background: Multiple myeloma (MM) presently remains largely incurable. The importance of circular RNAs (circRNAs) in various malignancies, including MM, has been demonstrated for decades. Our goal is to decipher the complex molecular mechanism of circ_0111738 in modulating MM progression.

Methods: Circ_0111738 and miR-1233-3p expressions in the collected MM cells and bone marrow aspirates were examined by qRT-PCR. CCK-8, transwell migration and invasion, and tube formation assays were performed to evaluate MM cell proliferation, migration and invasion, and angiogenesis, respectively. A tumor xenograft experiment was performed to validate the biofunction of circ_0111738's in vivo. The predicted interaction of circ_0111738 and miR-1233-3p's was determined by RNA immunoprecipitation (RIP) and luciferase reporter assays. Apoptosis-associated proteins and the HIF-1 pathway were investigated by western blotting.

Results: Circ_0111738 was poorly expressed in MM cells and patients. Overexpression of circ_0111738 reduced MM cell proliferation, migration, invasion, and angiogenesis while circ_0111738 led to opposite results. The anti-tumorigenic effect of circ_0111738 overexpression was also observed in vivo. RIP and luciferase experiments demonstrated that circ_0111738 interacted with miR-1233-3p in MM cells. The silencing of miR-1233-3p prevented the stimulation of malignant behaviors of MM cells induced by circ_0111738 silencing, including the expression of HIF-1α.

Conclusion: Our data suggest that circ_0111738 functioned as a competing endogenous RNA (ceRNA) and suppressed the oncogenic function of miR-1233-3p in MM by inactivating the HIF-1 pathway. Therefore, up-regulation of circ_0111738 may be a promising therapy against MM.

Keywords: Angiogenesis, Circ_0111738, Multiple myeloma; MiR-1233-3p.