Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
Second Department of Hepatobiliary, Surgery, ZhuJiang Hospital, Southern Medical University, China.
Cancer Lett. 2019 Mar 1;444:60-69. doi: 10.1016/j.canlet.2018.12.003. Epub 2018 Dec 21.
Hepatitis B virus X protein mutants, particularly truncated at C-terminal (HBxΔC), generated during random viral integration, are frequently detected in hepatocellular carcinoma (HCC) and exert a more potent oncogenic effect than full-length form (FL). Here, we showed that caveolin-1 (Cav1), a robust metastasis promoter, is transcriptionally upregulated by HBxΔC but not by FL HBx. Promoting effect of HBxΔC in HCC cell aggressiveness is abolished when Cav1 is suppressed. Expression profiling identified FERM domain containing 5 (FRMD5) protein as a downstream target of Cav1. In accordance with the regulation of Cav1, HBxΔC upregulates FRMD5. Knockdown of FRMD5 in HBxΔC cells recapitulated the functional effect of Cav1 knockdown in HBxΔC cells. The regulation of FRMD5 by HBxΔC-induced Cav1 is mediated by the protein stablilization of LRP6 leading to the activation of β-catenin. Expression of a constitutively active β-catenin in Cav1 knockdown cells rescued FRMD5 expression and HCC tumorigenesis and metastasis. Clinical relevance of HBxΔC/Cav1/LRP6/FRMD5 pathway is demonstrated by the significant correlation of Cav1, LRP6 and FRMD5 expressions in HCC. The findings of this study uncover a novel HBxΔC-regulated molecular pathway which has profound implications in HCC therapeutics.
乙型肝炎病毒 X 蛋白突变体，特别是在 C 末端截断的（HBxΔC），在随机病毒整合过程中产生，在肝细胞癌（HCC）中经常被检测到，并比全长形式（FL）具有更强的致癌作用。在这里，我们表明窖蛋白-1（Cav1），一种强大的转移促进剂，被 HBxΔC 而非 FL HBx 转录上调。当 Cav1 被抑制时，HBxΔC 在 HCC 细胞侵袭性中的促进作用被消除。表达谱分析确定 FERM 结构域包含 5（FRMD5）蛋白为 Cav1 的下游靶标。与 Cav1 的调节一致，HBxΔC 上调 FRMD5。在 HBxΔC 细胞中敲低 FRMD5 可重现 Cav1 在 HBxΔC 细胞中敲低的功能效应。HBxΔC 诱导的 Cav1 对 FRMD5 的调节是通过 LRP6 的蛋白质稳定介导的，导致 β-连环蛋白的激活。在 Cav1 敲低细胞中表达组成型激活的 β-连环蛋白可挽救 FRMD5 的表达和 HCC 的肿瘤发生和转移。通过 HCC 中 Cav1、LRP6 和 FRMD5 表达的显著相关性，证明了 HBxΔC/Cav1/LRP6/FRMD5 途径的临床相关性。本研究的发现揭示了一种新的 HBxΔC 调控的分子途径，对 HCC 的治疗具有深远的意义。
