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Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein.

ABSTRACT: 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 (HBx) in HBV-associated hepatocarcinogenesis attracted much attention in recent years, the role and molecular mechanism for HBx in hepatoma invasion and metastasis remains poorly understood. In the present study, we found that HBx 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-3? (PI3K/AKT/GSK-3?) signal pathway by HBx expression. Functional studies revealed that HBx expression could enhance hepatoma cell migration and invasion in vitro. Moreover, stable HBx expression could also facilitate intrahepatic and distant lung metastasis of HCC in a nude mice tumor metastasis model in vivo. The correlation between increased PI3K/AKT/GSK-3? 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 HBx in promoting epithelial-mesenchymal transition through Snail protein stabilization by activating PI3K/AKT/GSK-3? 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.

SUBMITTER: Liu H

PROVIDER: S-EPMC7659259 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein.

Liu Haiou H Xu Le L He Hongyong H Zhu Yu Y Liu Jing J Wang Shanshan S Chen Lin L Wu Qian Q Xu Jiejie J Gu Jianxin J

Cancer science 20121018 12

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 (HBx) in HBV-associated hepatocarcinogenesis attracted much attention in recent years, the role and molecular mechanism for HBx in hepatoma invasion and metastasis remains poorly understood. In the present study, we found that HBx expression could induce ...[more]

PMID: 22957763

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Project description:AimSphingosine kinase 1 (SPHK1) is involved in various cellular functions, including cell growth, migration, apoptosis, cytoskeleton architecture and calcium homoeostasis, etc. As an oncogenic kinase, SPHK1 is associated with the development and progression of cancers. The aim of this study was to investigate whether SPHK1 was involved in hepatocarcinogenesis induced by the hepatitis B virus X protein (HBx).MethodsThe expression of SPHK1 in hepatocellular carcinoma (HCC) tissue and hepatoma cells were measured using qRT-PCR and Western blot analysis. HBx expression levels in hepatoma cells were modulated by transiently transfected with HBx or psi-HBx plasmids. The SPHK1 promoter activity was measured using luciferase reporter gene assay, and the interaction of the transcription factor AP2α with the SPHK1 promoter was studied with chromatin immunoprecipitation assay. The growth of hepatoma cells was evaluated in vitro using MTT and colony formation assays, and in a tumor xenograft model.ResultsA positive correlation was found between the mRNA levels of SPHK1 and HBx in 38 clinical HCC samples (r=+0.727, P<0.01). Moreover, the expression of SPHK1 was markedly increased in the liver cancer tissue of HBx-transgenic mice. Overexpressing HBx in normal liver cells LO2 and hepatoma cells HepG2 dose-dependently increased the expression of SPHK1, whereas silencing HBx in HBx-expressing hepatoma cells HepG2-X and HepG2.2.15 suppressed SPHK1 expression. Furthermore, overexpressing HBx in HepG2 cells dose-dependently increased the SPHK1 promoter activity, whereas silencing HBx in HepG2-X cells suppressed this activity. In HepG2-X cells, AP2α was found to directly interact with the SPHK1 promoter, and silencing AP2α suppressed the SPHK1 promoter activity and SPHK1 expression. Silencing HBx in HepG2-X cells abolished the HBx-enhanced proliferation and colony formation in vitro, and tumor growth in vivo.ConclusionHBx upregulates SPHK1 through the transcription factor AP2α, which promotes the growth of human hepatoma cells.

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Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein.

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Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein.

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