CircRNA Circ-CCND1 Aggravates Hepatocellular Carcinoma Tumorigenesis by Regulating the miR-497-5p/HMGA2 Axis.

Abstract

Circular RNAs (circRNAs) are key regulators in hepatocellular carcinoma (HCC) tumorigenesis and development, yet it is unclear whether circ-CCND1 participates in regulating HCC progression. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for detecting the expressions of circ-CCND1, microRNA (miR) -497-5p, and high mobility group AT-hook 2 (HMGA2) mRNA in HCC tissues and cell lines. Subcellular fractionation assay was used to analyze the localization of circ-CCND1 in HCC cell lines. Loss-of-function experiments were conducted to examine the effects of circ-CCND1 on HCC cell proliferation, migration, and invasion. Dual-luciferase reporter gene assay was employed for detecting the targeting relationships of circ-CCND1 and miR-497-5p, as well as miR-497-5p and HMGA2, respectively. Western blot was used to detect the regulatory functions of circ-CCND1 and miR-497-5p on HMGA1 expression at protein level. Circ-CCND1 and HMGA2 expressions in HCC were significantly up-regulated and miR-497-5p expression was markedly decreased. High circ-CCND1 expression was associated with relatively large tumor size and lymph node metastasis in HCC patients. In addition, circ-CCND1 was mainly distributed in the cytoplasm of HCC cells. Functionally, knockdown of circ-CCND1 remarkably suppressed HCC cell proliferation, migration, and invasion. Mechanistically, miR-497-5p was a direct target of circ-CCND1 and miR-497-5p specifically modulated HMGA2 expression. Furthermore, miR-497-5p inhibitors and or HMGA2 overexpression partially counteracted the suppressing effect induced by si-circ-CCND1 on the malignant phenotype of HCC cells. Circ-CCND1 plays a cancer-promoting role in HCC by modulating the miR-497-5p/HMGA2 axis. Therefore, targeting circ-CCND1 is likely to be a promising therapeutic strategy for HCC.