Zhu Yanqing, Zhu Yifei, Deng Qinyi, Liang Xin
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Eur J Pharmacol. 2025 Mar 15;991:177315. doi: 10.1016/j.ejphar.2025.177315. Epub 2025 Jan 28.
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors, often with a poor prognosis. The HBx protein, encoded by the hepatitis B virus (HBv), is significantly associated with the pathogenesis of HCC. Although studies suggested that the von Willebrand factor (vWF) is key to the progression of HCC associated with HBv, the underlying mechanisms are largely obscure. Here we report that high vWF expression predicts poor prognosis in HCC patients infected with HBv. In vitro studies have shown that vWF enhances the migration, invasion, proliferation, and epithelial-mesenchymal transition (EMT) of HCC associated with HBv, and also inhibits apoptosis. We demonstrated that HBv-encoded oncogene X protein (HBx), a core protein of HBv expression can facilitate the transcription of vWF through the upregulation of ASCL1. Furthermore, miR-3150b-3p, which is negatively regulated by HBx, was screened to bind to the 3'UTR of ASCL1 and mediate ASCL1 silencing. Finally, we found that ST8SIA6-AS1 is positively regulated by HBx, which could sponge miR-3150b-3p, consequently impacting the expression of ASCL1 and ultimately alters the protein levels of vWF. In conclusion, our study identified that Hepatitis B Virus X Protein affected vWF level in HBv-related HCC through ST8SIA6-AS1/miR-3150b-3p/ASCL1 axis, which in turn promoted tumor malignant progression.
肝细胞癌（HCC）是最常见的恶性肿瘤之一，预后通常较差。由乙型肝炎病毒（HBv）编码的HBx蛋白与HCC的发病机制密切相关。尽管研究表明血管性血友病因子（vWF）是与HBv相关的HCC进展的关键因素，但其潜在机制仍 largely obscure。在这里，我们报告高vWF表达预示着感染HBv的HCC患者预后不良。体外研究表明，vWF增强了与HBv相关的HCC的迁移、侵袭、增殖和上皮-间质转化（EMT），并抑制细胞凋亡。我们证明，HBv编码的癌基因X蛋白（HBx），即HBv表达的核心蛋白，可通过上调ASCL1促进vWF的转录。此外，筛选出受HBx负调控的miR-3150b-3p，其可与ASCL1的3'UTR结合并介导ASCL1沉默。最后，我们发现ST8SIA6-AS1受HBx正调控，其可吸附miR-3150b-3p，从而影响ASCL1的表达，最终改变vWF的蛋白水平。总之，我们的研究发现，乙型肝炎病毒X蛋白通过ST8SIA6-AS1/miR-3150b-3p/ASCL1轴影响HBv相关HCC中的vWF水平，进而促进肿瘤恶性进展。
