N6-methyladenosine modification of circular RNA circ-ARL3 facilitates Hepatitis B virus-associated hepatocellular carcinoma via sponging miR-1305

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.

Automated summary

The study identified a HBV-related circRNA, circ-ARL3, and demonstrated that silencing this circRNA inhibited the proliferation and invasion of HBV+ HCC cells, and was correlated with malignant clinical features and poor prognosis. Mechanistically, HBx protein upregulated METTL3 expression to increase m(6)A modification of circ-ARL3, promoting HBV+ HCC progression.