大量文献，包括我们自己的文献，都指出乙型肝炎病毒 (HBV) 感染与肝细胞癌 (HCC) 耐药性的发展之间存在联系，特别是对索拉非尼的耐药性。然而，乙型肝炎病毒对另一种治疗药物瑞格非尼耐药性的影响研究较少。在本研究中，我们使用 GEO 数据库 (GSE87630) 和临床样本证明 C-C 基序趋化因子受体 9 (CCR9) 在 HBV 相关 HCC 中高表达，并预测总体生存率较差。其过度表达与 HBsAg 阳性 HCC 患者相关。单变量和多变量 Cox 回归分析均表明 CCR9 是 HCC 患者总生存率较差的独立危险因素。我们的体外研究结果进一步表明，HBV 结构蛋白、小 HBV 表面抗原 (SHB) 引发了 CCR9 的上调。功能测定表明，SHB 增强 HCC 细胞增殖、迁移和侵袭，增加 ABCB1 和 ABCC1 表达，并通过 CCR9 促进瑞格非尼耐药。有趣的是，HBV 质粒的过度表达和 AAV-HBV 小鼠模型均表现出整体 N6-甲基腺苷 (m6A) 水平的显着升高。进一步的研究表明，SHB 通过 KIAA1429 介导的 m6A 修饰提高这些 m6A 水平、上调 CCR9 并稳定 CCR9 mRNA，其中 CCR9 mRNA 上的位点 1373 和 1496 对于修饰至关重要。总之，SHB 通过 KIAA1429 介导的 CCR9 m6A 修饰促进 HCC 进展和瑞格非尼耐药。我们的研究结果表明，CCR9 可能是 HBV 相关 HCC 中瑞戈非尼耐药的潜在预后生物标志物和有价值的分子治疗靶点。© 2024 Wiley periodicals LLC。

A substantial body of literature, including our own, points to a connection between hepatitis B virus (HBV) infection and the development of drug resistance in hepatocellular carcinoma (HCC), particularly against sorafenib. However, the influence of HBV on resistance to regorafenib, another therapeutic agent, has been less studied. In this study, we used the GEO database (GSE87630) and clinical samples to demonstrate that C-C motif chemokine receptor 9 (CCR9) was highly expressed in HBV-related HCC and predicted poor overall survival. Its overexpression correlated with HBsAg-positive HCC patients. Both univariate and multivariable Cox regression analysis elucidated CCR9 was an independent risk factor for poor overall survival in HCC patients. Our in vitro findings further revealed that HBV structural proteins, small HBV surface antigen (SHBs), triggered an upregulation of CCR9. Functional assays showed that SHBs enhanced HCC cell proliferation, migration, and invasion, increased ABCB1 and ABCC1 expression, and promoted regorafenib resistance via CCR9. Intriguingly, overexpression of HBV plasmid and an AAV-HBV mouse model both exhibited a significant elevation in global N6-methyladenosine (m6A) levels. Further investigations revealed that SHBs elevated these m6A levels, upregulated CCR9 and stabilized CCR9 mRNA through KIAA1429-mediated m6A modification, with sites 1373 and 1496 on CCR9 mRNA being critical for modification. In conclusion, SHBs promoted HCC progression and regorafenib resistance via KIAA1429-mediated m6A modification of CCR9. Our findings suggested that CCR9 could be a potential prognostic biomarker and a valuable molecular therapeutic target of regorafenib resistance in HBV-related HCC.© 2024 Wiley Periodicals LLC.