Expression of mutated hepatitis B virus X genes in human hepatocellular carcinomas

Poussin, Karine; Dienes, Hans Peter; Sirma, Hüseyin; Urban, S.; Beaugrand, Michel; Franco, Dominique; Schirmacher, Peter; Bréchot, Christian; Bréchot, Patrizia Paterlini

doi:10.1002/(sici)1097-0215(19990209)80:4<497::aid-ijc3>3.0.co;2-8

Cited by 88 publications

(55 citation statements)

References 43 publications

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“…Finally, our group has identified a high rate of mutations in the HBx ORF gene in the tumor tissue from such HBsAg-negative, HBV DNA-positive patients; this high rate of amino-acid changes contrasted with a lower rate of mutations in PreC:C sequences . In addition, PCR has allowed us to detect the expression of the HBx RNA in such tumors (Paterlini et al, 1995;Poussin et al, 1999). Similar results were reported in Japan (Tamori et al, 1999).…”

Section: Hbv-related Hcc D Kremsdorf Et Alsupporting

confidence: 74%

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

et al. 2006

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As discussed in detail in other chapters of this review, chronic hepatitis B (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Most HCCs complicate the evolution of an active or inactive cirrhosis. However, some tumors occur on livers with minimal histological changes; the prevalence of such cases varies from one geographical region to the other, being much higher in the southern half of Africa (around 40% of HCCs) than in Asia, America and Europe, where at least 90% of HCCs are associated with the cirrhosis. This heterogeneity is probably a reflection of different environmental and genetic factors. This review will summarize the current knowledge on the mechanisms involved in HBVrelated liver carcinogenesis. It will show in particular how viruses can be viewed as tools to discover and dissect new cellular pathways involved in cancer development and emphasize the potential synergistic effects between HBV and hepatitis C virus, as well as between viral infections and other environmental factors, such as alcohol.

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Section: Hbv-related Hcc D Kremsdorf Et Alsupporting

confidence: 74%

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

et al. 2006

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“…These data are consistent with HBx mutations impacting on early steps of liver carcinogenesis, an issue which will now be testable in chronically infected subjects without HCC. We have previously shown that HCC tissue cells continue to transcribe and express HBx RNA and protein, respectively, despite extinction of HBV envelope and capsid proteins expression (Poussin et al, 1999;Paterlini et al, 1995). Our present data lead to hypothesize that, at least in some HCC tissues, this protein may be functionally inactivated by mutations and/or deletions.…”

Section: Discussionsupporting

confidence: 51%

“…Isolation and characterization of X-ORFs from the tumoral and nontumoral tissues from patients with HCC has been reported in detail elsewhere (Poussin et al, 1999) Brie¯y, DNA was extracted from frozen tumoral tissues from four patients with HCC, one of these being HBsAg positive and three HBsAg negative, but HBV DNA positive in the liver samples. To distinguish between integrated HBV genomes from replicative viral genomes, with potentially very di erent biological e ects, we combined two approaches: we studied HCCs in which the pregenomic HBV RNA was undetectable by RT ± PCR (for the HBsAg negative cases : patients C, M and F) and we used an Alu ± PCR based assay (for the HBsAg positive case referred as GT) (Minami et al, 1995).…”

Section: Plasmids and Hbx Sequencesmentioning

confidence: 99%

Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

et al. 1999

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Chronic infection by HBV is the leading cause of hepatocellular carcinoma in man. Several lines of evidence suggest that the viral transactivator HBx plays a critical role in the molecular pathogenesis of HBVrelated HCC. To study the actual impact of HBx and the mechanism of its action, we have recently cloned and characterized a set of X-sequences from HCC in patients with chronic infection by HBV. In the present study, we have compared the e ects of HBx and its naturally arising mutants on cell growth and viability. We report that HBx inhibits clonal outgrowth of cells and induces apoptosis by a p53-independent pathway. Furthermore, HBx expression induced a late G1 cell cycle block prior to their counterselection by apoptosis. Importantly, mutations in the HBx-gene evolving in hepatocellular carcinoma abolished both HBx-induced growth arrest and apoptosis. Using a panel of engineered mutants we have mapped the growth suppressive e ect of HBx to domains shown to be required for its transactivating function. Based on these results, we propose that abrogation of the anti-proliferative and apoptotic e ects of HBx by naturally occurring mutations might render the hepatocytes susceptible to uncontrolled growth and contribute to multistep hepatocarcinogenesis associated with HBV-infection.

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“…Although HBx expression is often detected in HBV-related HCCs (Feitelson and Duan, 1997), the prognosis and/or prevalence of metastasis of HBx-expressing tumors has not been studied so far. In addition, it has been shown that the X gene is often mutated in HCCs Baptista et al, 1999;Poussin et al, 1999). However, these mutations accumulate preferently within the transactivation domains of HBx, without a ecting HBx-mediated cell transformation (Gottlob et al, 1998b).…”

Section: Discussionmentioning

confidence: 99%

The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner

et al. 2001

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Chronic hepatitis B virus infection is strongly associated with the development of hepatocellular carcinoma (HCC). Epithelial tumors are frequently characterized by loss of cadherin expression or function. Cadherindependent adhesion prevents the acquisition of a migratory and invasive phenotype, and loss of its function is itself enough for the progression from adenoma to carcinoma. The HBx protein of hepatitis B virus is thought to contribute to the development of the carcinoma, however, its role in the oncogenic and metastatic processes is far from being fully understood. We report herein the ability of HBx to disrupt intercellular adhesion in three di erent cell lines stably transfected with an inducible HBx expression vector. The linkage between the actin cytoskeleton and cadherin complex, which is essential for its function, is disrupted in the presence of HBx, as indicated by detergent solubility and immunoprecipitation experiments. In addition, b-catenin was tyrosine phosphorylated in HBx-expressing cells. Inhibition of the src family of tyrosine kinases resulted in the prevention of the disruption of adherens junctions. These results suggest that HBx is able to disrupt intercellular adhesion in a src-dependent manner, and provide a novel mechanism by which HBx may contribute to the development of HCC. Oncogene (2001) 20, 3323 ± 3331.

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Expression of mutated hepatitis B virus X genes in human hepatocellular carcinomas

Cited by 88 publications

References 43 publications

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner

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