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.

中文翻译：

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环状 RNA circ-ARL3 的 N 6-甲基腺苷修饰通过海绵状 miR-1305 促进乙型肝炎病毒相关的肝细胞癌

乙型肝炎病毒（HBV）感染是肝细胞癌（HCC）的主要危险因素，环状RNA（circRNA）是否参与这一过程尚不清楚。在这项研究中，我们进行了 circRNA 微阵列分析，发现了一个与 HBV 相关的 circRNA，circ-ARL3 (hsa_circ_0092493)。circ-ARL3 的稳定敲低抑制了 HBV+ HCC 细胞的增殖和侵袭。高circ-ARL3与恶性临床特征和预后不良呈正相关。机制上，HBx蛋白上调N6-甲基腺苷（m6 A）甲基转移酶METTL3的表达，增加circ-ARL3的m6 A修饰；然后，m6 A 阅读器 YTHDC1 与 m6 A 修饰的 circ-ARL3 结合，并有利于其反向剪接和生物发生。此外，circ-ARL3 能够吸附 miR-1305，拮抗 miR-1305 对一组靶癌基因的抑制作用，从而促进 HBV + HCC 进展。重要的是，circ-ARL3 的消耗显着延缓了体内 HBV + HCC 细胞的生长，而在 miR-1305 沉默后这种作用明显被阻断。总的来说，我们的数据表明 circ-ARL3 是 HBV 相关 HCC 的关键调节因子，靶向 circ-ARL3/miR-1305 轴可能是 HBV+ HCC 患者的一种有希望的治疗方法。