Wu Shuxiang, Hong Yuxiang, Li Hang, Lin Mengxian, Lin Xiaohuang, Lin Xinjian, Lin Xu
Key Laboratory of Gastrointestinal Cancer, (Fujian Medical University), Ministry of Education, Fuzhou, China.
Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
Cancer Sci. 2025 Sep;116(9):2471-2485. doi: 10.1111/cas.70132. Epub 2025 Jun 28.
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide, with a significant association to hepatitis B virus (HBV) infection, which has been shown to drive HCC progression. Sorafenib, a multi-kinase inhibitor, is the first-line treatment for advanced HCC. However, recent studies indicate that HBV infection may confer resistance to sorafenib treatment. The small hepatitis B surface antigen (SHBs), the most abundant HBV viral protein, has been implicated in HCC development, yet its role in sorafenib resistance is unclear. This study demonstrates that SHBs promotes sorafenib resistance in HCC cells and xenograft models by inhibiting apoptosis. Upon sorafenib treatment, SHBs expression was found to enhance the RAF1/MEK/ERK signaling pathway, as evidenced by increased phosphorylation of ERK and MEK. Inhibition of ERK activity with U0126 countered SHBs effects on sorafenib-induced apoptosis, cleaved caspase-3, and cellular proliferation. Mechanistically, SHBs binds to protein tyrosine phosphatase non-receptor type 1 (PTPN1), enhancing its phosphorylation, which subsequently dephosphorylates the protein tyrosine phosphatase interacting protein 51 (PTPIP51). This dephosphorylation promotes RAF1 recruitment to the 14-3-3β complex, leading to activation of the RAF1/MEK/ERK pathway. These findings suggest that SHBs prevents sorafenib-induced apoptosis in HCC cells by binding to PTPN1 and stimulating the formation of the PTPIP51/14-3-3β/RAF1 complex, thereby activating the RAF1/MEK/ERK signaling pathway. This mechanism provides insight into HBV-induced sorafenib resistance in HCC, highlighting SHBs as a potential target for overcoming treatment resistance in HBV-related HCC.
肝细胞癌（HCC）是全球最常见的癌症之一，与乙型肝炎病毒（HBV）感染密切相关，HBV感染已被证明会推动HCC进展。索拉非尼是一种多激酶抑制剂，是晚期HCC的一线治疗药物。然而，最近的研究表明，HBV感染可能使肝癌细胞对索拉非尼治疗产生耐药性。小乙肝表面抗原（SHBs）是最丰富的HBV病毒蛋白，与HCC的发生有关，但其在索拉非尼耐药中的作用尚不清楚。本研究表明，SHBs通过抑制细胞凋亡促进HCC细胞和异种移植模型对索拉非尼的耐药性。在索拉非尼治疗后，发现SHBs表达增强了RAF1/MEK/ERK信号通路，ERK和MEK磷酸化增加证明了这一点。用U0126抑制ERK活性可对抗SHBs对索拉非尼诱导的细胞凋亡、裂解的caspase-3和细胞增殖的影响。从机制上讲，SHBs与非受体型蛋白酪氨酸磷酸酶1（PTPN1）结合，增强其磷酸化，随后使蛋白酪氨酸磷酸酶相互作用蛋白51（PTPIP51）去磷酸化。这种去磷酸化促进RAF1募集到14-3-3β复合物，导致RAF1/MEK/ERK通路激活。这些发现表明，SHBs通过与PTPN1结合并刺激PTPIP51/14-3-3β/RAF1复合物的形成，从而激活RAF1/MEK/ERK信号通路，阻止索拉非尼诱导的HCC细胞凋亡。这一机制为HBV诱导的HCC索拉非尼耐药提供了深入了解，突出了SHBs作为克服HBV相关HCC治疗耐药性的潜在靶点。
