ETV4 mediates the Wnt/β-catenin pathway through transcriptional activation of ANXA2 to promote hepatitis B virus-associated liver hepatocellular carcinoma progression

Abstract

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.

Keywords: ANXA2; ETV4; Wnt/β-catenin pathway; hepatitis B virus; liver hepatocellular carcinoma.