<scp>N⁶</scp>‐methyladenosine modification of circular <scp>RNA circ‐ARL3</scp> facilitates <scp>Hepatitis B virus</scp>‐associated hepatocellular carcinoma via sponging <scp>miR</scp>‐1305

Abstract

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 N⁶ -methyladenosine (m⁶ A) methyltransferases METTL3 expression, increasing the m⁶ A modification of circ-ARL3; then, m⁶ A reader YTHDC1 bound to m⁶ 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.