Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), whether circular RNA (circRNA) is involved in this process remains unknown. In this study, we performed circRNA microarray profile and found an HBV-related circRNA, circ-ARL3 (hsa_circ_0092493). Stable knockdown of circ-ARL3 inhibited the proliferation and invasion of HBV^{+} HCC cells. High circ-ARL3 was positively correlated with malignant clinical features and poor prognosis. In terms of mechanism, HBx protein upregulated N^{6} -methyladenosine (m^{6} A) methyltransferases METTL3 expression, increasing the m^{6} A modification of circ-ARL3; then, m^{6} A reader YTHDC1 bound to m^{6} A-modified of circ-ARL3 and favored its reverse splicing and biogenesis. Furthermore, circ-ARL3 was able to sponge miR-1305, antagonizing the inhibitory effects of miR-1305 on a cohort of target oncogenes, thereby promoting HBV^{+} HCC progression. Importantly, depletion of circ-ARL3 significantly retarded HBV^{+} HCC cell growth in vivo, whereas this effect was evidently blocked after silencing of miR-1305. Collectively, our data suggest that circ-ARL3 is a critical regulator in HBV-related HCC, targeting the axis of circ-ARL3/miR-1305 may be a promising treatment for HBV^{+} HCC patients.
【저자키워드】 circRNA, Hepatitis B virus, Hepatocellular carcinoma, N6-methyladenosine, miRNA sponge.,