Hepatitis B Virus Promotes Angiogenesis in Hepatocellular Carcinoma by Increasing m6A Modification of VEGFA mRNA via IGF2BP3

Angiogenesis plays a crucial role in the development of HBV-related hepatocellular carcinoma (HCC). VEGFA is a key angiogenic factor, and while its transcriptional regulation by HBV has been extensively studied, its posttranscriptional regulation by HBV remains poorly understood. Building on our previous findings that delineated an RBM15/YTHDF2/IGF2BP3 regulatory axis in m6A-mediated RNA metabolism in HCC, this study further explores the posttranscriptional regulation of VEGFA by HBV. By MeRIP-qPCR and integrating MeRIP-seq data, we discovered that HBV enhances m6A methylation of VEGFA mRNA. Comprehensive cellular and Molecular Biology experiments demonstrated that HBV induces the upregulation of IGF2BP3, which serves as a key "reader" that recognizes and stabilizes VEGFA mRNA in an m6A methylation-dependent manner. This stabilization leads to elevated VEGFA expression, promoting enhanced cellular functions such as HUVEC migration and tube formation. Furthermore, in an HBV-associated HCC xenograft model, IGF2BP3 knockdown resulted in decreased VEGFA expression and inhibited tumor growth. This study expands our understanding of HBV-driven angiogenesis and identifies the IGF2BP3-VEGFA axis as a potential therapeutic target for antiangiogenic strategies in HBV-related HCC.

HBV; VEGFA; angiogenesis; hepatocellular carcinoma; m6A modification.