Hepatitis B virus (HBV) is a major risk factor for the development and progression of hepatocellular carcinoma (HCC). It has been reported that viral infection can interfere with the expression of cellular microRNA (miRNA) to affect oncogenesis. In this study, we showed that miR-520c-3p was upregulated in liver tumor specimens, and we revealed that HBV infection enhanced the expression of miR-520c-3p through the interaction of viral protein HBV X protein (HBx) with transcription factor CREB1. We further showed that miR-520c-3p induced by HBV transfection/infection caused epithelial-mesenchymal transition (EMT). Using the miRNA target prediction database miRBase and luciferase reporter assays, we identified PTEN as a novel target gene of miR-520c-3p and miR-520c-3p directly targeted PTEN’s 3′-untranslated region. Moreover, we discovered that HBV promoted EMT via the miR-520c-3p-PTEN to activate AKT-NFκB signaling pathway, leading to increased HCC migration and invasion. Importantly, miR-520c-3p antagomir significantly represses invasiveness in HBx-induced hepatocellular xenograft models. Our findings indicate that miR-520c-3p is a novel regulator of HBV and plays an important role in HCC progression. It may serve as a new biomarker and molecular therapeutic target for HBV patients.

乙型肝炎病毒（HBV）是肝细胞癌（HCC）发生和发展的主要危险因素。据报道，病毒感染可干扰细胞微小RNA（miRNA）的表达以影响肿瘤发生。在这项研究中，我们发现 miR-520c-3p 在肝肿瘤标本中上调，我们发现 HBV 感染通过病毒蛋白 HBV X 蛋白 (HBx) 与转录因子 CREB1 的相互作用增强了 miR-520c-3p 的表达。 . 我们进一步表明由HBV转染/感染诱导的miR-520c-3p引起上皮-间质转化（EMT）。使用 miRNA 靶点预测数据库 miRBase 和荧光素酶报告基因分析，我们将 PTEN 鉴定为 miR-520c-3p 的新靶基因，并且 miR-520c-3p 直接靶向 PTEN 的 3'-非翻译区。而且，我们发现HBV通过miR-520c-3p-PTEN促进EMT激活AKT-NFκB信号通路，导致HCC迁移和侵袭增加。重要的是，miR-520c-3p antagomir 显着抑制 HBx 诱导的肝细胞异种移植模型的侵袭性。我们的研究结果表明，miR-520c-3p 是一种新型的 HBV 调节因子，在 HCC 进展中起重要作用。它可能作为HBV患者的新生物标志物和分子治疗靶点。