Circular RNA circZFR Promotes Hepatocellular Carcinoma Progression by Regulating miR-375/HMGA2 Axis

Abstract

Mounting evidence indicates that circular RNAs (circRNAs) have vital roles in human diseases, especially in cancers. The aim of this study was to explore the biological functions and underlying mechanism of circRNA zinc finger RNA binding (circZFR) in hepatocellular carcinoma (HCC). The expression levels of circZFR, microRNA-375 (miR-375) and high mobility group A2 (HMGA2) were detected by qRT-PCR or western blot assay. Glycolytic metabolism was examined via the measurement of extracellular acidification rate, oxygen consumption rate, glucose uptake, lactate production, and ATP level. MTT assay and flow cytometry were used to assess cell proliferation and cell apoptosis, respectively. The interaction between miR-375 and circZFR or HMGA2 was verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. The mice xenograft model was established to investigate the role of circZFR in vivo. CircZFR and HMGA2 were upregulated while miR-375 was downregulated in HCC tissues and cells. CircZFR silence inhibited HCC progression by inhibiting cell proliferation, glycolysis and tumor growth and promoting apoptosis. MiR-375 was a direct target of circZFR and its knockdown reversed the inhibitory effect of circZFR silence on the progression of HCC cells. Moreover, HMGA2 was a downstream target of miR-375, and miR-375 suppressed proliferation and glycolysis and induced apoptosis by targeting HMGA2 in HCC cells. Besides, circZFR acted as a molecular sponge of miR-375 to regulate HMGA2 expression. Knockdown of circZFR suppressed the progression of HCC by upregulating miR-375 and downregulating HMGA2, providing new insight into the pathogenesis of HCC.