ETS variant 4 (ETV4) has been implicated in the development of various cancers. However, the molecular events mediated by ETV4 in liver cancer are poorly understood, especially in hepatitis B virus (HBV)-associated liver hepatocellular carcinoma (LIHC). Here, we aimed to identify the target involved in ETV4-driven hepatocarcinogenesis. Bioinformatics analysis revealed that ETV4 was highly expressed in patients with HBV-associated LIHC, and HBV infection promoted the expression of ETV4 in LIHC cells. Inhibition of ETV4 repressed the proliferation, migration, invasion of LIHC cells and suppressed the secretion of HBV and the replication of HBV DNA. ANXA2 expression in LIHC patients was positively correlated with ETV4 expression. Chromatin immunoprecipitation and dual-luciferase reporter assays revealed that ETV4 elevated the ANXA2 expression at the transcriptional level by binding to the ANXA2 promoter. Overexpression of ANXA2 reversed the inhibitory effect of sh-ETV4 on the malignant biological behaviours of HBV-infected LIHC cells by activating the Wnt/β-catenin pathway. In conclusion, ETV4 mediates the activation of Wnt/β-catenin pathway through transcriptional activation of ANXA2 expression to promote HBV-associated LIHC progression.

中文翻译：

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ETV4通过ANXA2的转录激活介导Wnt/β-catenin通路促进乙型肝炎病毒相关肝细胞癌进展

ETS 变体 4 (ETV4) 与各种癌症的发展有关。然而，人们对 ETV4 在肝癌中介导的分子事件知之甚少，尤其是在乙型肝炎病毒 (HBV) 相关的肝细胞癌 (LIHC) 中。在这里，我们旨在确定参与 ETV4 驱动的肝癌发生的靶标。生物信息学分析显示ETV4在HBV相关LIHC患者中高表达，HBV感染促进了LIHC细胞中ETV4的表达。抑制 ETV4 可抑制 LIHC 细胞的增殖、迁移和侵袭，抑制 HBV 的分泌和 HBV DNA 的复制。LIHC 患者中 ANXA2 的表达与 ETV4 的表达呈正相关。染色质免疫沉淀和双荧光素酶报告基因分析表明，ETV4 通过与 ANXA2 启动子结合，在转录水平上提高了 ANXA2 的表达。ANXA2的过表达通过激活Wnt/β-catenin通路逆转了sh-ETV4对HBV感染的LIHC细胞恶性生物学行为的抑制作用。总之，ETV4通过ANXA2表达的转录激活介导Wnt/β-catenin通路的激活，从而促进HBV相关的LIHC进展。