GPC3‐CD81 axis in the HCV mediated liver carcinogenesis

Abstract

Glypican‐3 (GPC3) is highly over‐expressed in human hepatocellular carcinomas (HCC). GPC3 decreases liver regeneration by interacting with CD81. Other groups have shown that activation of CD81 increases phosphorylation of Ezrin (p‐Ezrin), which inhibits Hippo pathway. Hepatitis C virus (HCV) interacts with human CD81 by E2 protein to enter into hepatocytes. We investigated the mechanism of HCV and GPC3‐CD81 axis in liver carcinogenesis. HepaRG human hepatoma cell line was treated with E2 protein to evaluate the Hippo activity. Rat hepatocytes were treated with CD81 agonist antibody to determine if CD81 related Hippo activity depends on p‐Ezrin. Partial hepatectomy (PHx) was used to evaluate the dynamic changes of GPC3‐CD81 axis with Hippo activity. Human and rat HCC cell lines were used to define GPC3‐CD81 interactions. HCC tissue array was used to assess the expression characteristic of CD81‐GPC3. After E2 treatment, Hepa RG cells had higher activity of Hippo. Treatment of rat hepatocytes with CD81 agonist antibody led to lower Hippo activity and higher p‐Ezrin. PHx shows that GPC3 increases at the early stage of liver regeneration while CD81 decreases, while Yap activity increases. Both human and rat HCC cell lines have dramatically decreased CD81 expression levels. HCC tissue array also shows absence of CD81 in most HCC.ConclusionsDependent on CD81, GPC3 may function as tumor‐suppressor gene by modulating YAP expression. Persistent E2 HCV protein interacts with CD81 to decrease Yap via Hippo. Hepatocytes with no expression of CD81 would have a growth advantage to undergo clonal expansion, facilitating formation of HCC. After absence of CD81, GPC3 may be unable to control the Hippo, and this maybe the reason for its high expression in HCC.