Open AccessHepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing S nail protein
Author(s) -
Liu Haiou,
Xu Le,
He Hongyong,
Zhu Yu,
Liu Jing,
Wang Shanshan,
Chen Lin,
Wu Qian,
Xu Jiejie,
Gu Jianxin
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12017
Subject(s) - protein kinase b , metastasis , cancer research , epithelial–mesenchymal transition , biology , hepatocellular carcinoma , hepatitis b virus , protein kinase a , gsk 3 , signal transduction , kinase , immunology , cancer , virus , microbiology and biotechnology , genetics
A high incidence of tumor recurrence and metastasis has been reported in hepatocellular carcinoma ( HCC ) patients with chronic hepatitis B virus ( HBV ) infection. Although the pathological relevance and significance of hepatitis B virus X protein ( HB x) in HBV ‐associated hepatocarcinogenesis attracted much attention in recent years, the role and molecular mechanism for HB x in hepatoma invasion and metastasis remains poorly understood. In the present study, we found that HB x expression could induce epithelial–mesenchymal transition in hepatoma and hepatic cells. This effect was shown due to stabilized Snail protein through activating the phosphatidylinositol 3‐kinase/protein kinase B /glycogen synthase kinase‐3β ( PI 3K/ AKT / GSK ‐3β) signal pathway by HB x expression. Functional studies revealed that HB x expression could enhance hepatoma cell migration and invasion in vitro . Moreover, stable HB x expression could also facilitate intrahepatic and distant lung metastasis of HCC in a nude mice tumor metastasis model in vivo . The correlation between increased PI 3K/ AKT / GSK ‐3β signaling with elevated Snail protein level was also observed in HCC tumor tissues with intrahepatic metastasis or chronic HBV infection. These results revealed a novel function of HB x in promoting epithelial–mesenchymal transition through Snail protein stabilization by activating PI 3K/ AKT / GSK ‐3β signaling, thus facilitating tumor invasion and metastasis during HCC progression. This could provide a putative molecular mechanism for tumor recurrence and metastasis in HBV ‐associated HCC patients.