Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Am J Pathol. 2018 Jun;188(6):1469-1477. doi: 10.1016/j.ajpath.2018.02.013. Epub 2018 Mar 22.
Glypican (GPC)-3 is overexpressed in hepatocellular carcinomas (HCCs). GPC3 binds to CD81. Forced expression of CD81 in a GPC3-expressing HCC cell line caused activation of Hippo, a decrease in ezrin phosphorylation, and a decrease in yes-associated protein (YAP). CD81 is also associated with hepatitis C virus (HCV) entry into hepatocytes. Activation of CD81 by agonistic antibody causes activation of tyrosine-protein kinase SYK (SYK) and phosphorylation of ezrin, a regulator of the Hippo pathway. In cultures of normal hepatocytes, CD81 agonistic antibody led to enhanced phosphorylation of ezrin and an increase in nuclear YAP. HCV E2 protein mimicked GPC3 and led to enhanced Hippo activity and decreased YAP in cultured normal human hepatocytes. HCC tissue microarray revealed a lack of expression of CD81 in most HCCs, rendering them insusceptible to HCV infection. Activation of CD81 by agonistic antibody suppressed the Hippo pathway and increased nuclear YAP. HCV mimicked GPC3, causing Hippo activation and a decrease in YAP. HCV is thus likely to enhance hepatic neoplasia by acting as a promoter of growth of early CD81-negative neoplastic hepatocytes, which are resistant to HCV infection, and thus have a proliferative advantage to clonally expand as they participate in compensatory regeneration for the required maintenance of 100% of liver weight (hepatostat).
磷脂酰聚糖 3（GPC）在肝细胞癌（HCC）中过度表达。GPC3 与 CD81 结合。在表达 GPC3 的 HCC 细胞系中强制表达 CD81 会导致 Hippo 激活、ezrin 磷酸化减少和 yes 相关蛋白（YAP）减少。CD81 也与丙型肝炎病毒（HCV）进入肝细胞有关。激动型抗体激活 CD81 会导致酪氨酸蛋白激酶 SYK（SYK）激活和 Hippo 通路调节剂 ezrin 磷酸化。在正常肝细胞培养物中，CD81 激动型抗体导致 ezrin 磷酸化增强和核 YAP 增加。HCV E2 蛋白模拟 GPC3，导致培养的正常人肝细胞中 Hippo 活性增强和 YAP 减少。HCC 组织微阵列显示大多数 HCC 中缺乏 CD81 表达，使其对 HCV 感染不敏感。激动型抗体激活 CD81 会抑制 Hippo 通路并增加核 YAP。HCV 模拟 GPC3，导致 Hippo 激活和 YAP 减少。因此，HCV 可能通过作为早期 CD81 阴性肿瘤性肝细胞生长的促进剂来增强肝肿瘤发生，这些细胞对 HCV 感染具有抗性，因此在参与所需的 100%肝重量（肝稳态）维持的代偿性再生时具有克隆扩增的增殖优势。
