Neuveut C, Wei Y, Buendia MAMechanisms of HBV-related hepatocarcinogenesis. J Hepatol 52: 594-604

Oncogenesis and Molecular Virology Unit, Institut Pasteur, Inserm U579, 28 rue du Dr Roux, Paris cedex 15, France.
Journal of Hepatology (Impact Factor: 11.34). 04/2010; 52(4):594-604. DOI: 10.1016/j.jhep.2009.10.033
Source: PubMed


The hepatitis B virus (HBV) is a small enveloped DNA virus, which primarily infects hepatocytes and causes acute and persistent liver disease. Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma, but the molecular mechanisms underlying virally-induced tumourigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, indirect roles have been proposed, including insertional activation of cellular cancer-related genes by HBV DNA integration, induction of genetic instability by viral integration or by the regulatory protein HBx, and long-term effects of viral proteins in enhancing immune-mediated liver disease. Recent genetic studies indicate that HBV-related tumours display a distinctive profile with a high rate of chromosomal alterations and low frequency of beta-catenin mutations. This review will discuss the evidence implicating chronic HBV infection as a causal risk factor of primary liver cancer. It will also discuss the molecular mechanisms that are critical for the tumourigenic process due to long lasting infection with HBV.

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    • "An essential role of HBx in the viral life cycle is to activate HBV transcription. This activity involves multiple interactions with cellular partners and might be responsible for the wide range of functions attributed to HBx, as for other viral transactivators (Neuveut et al. 2010). The transactivation of cellular oncogenes and growth factors leading to aberrant oncogenic signaling and the deregulation of cell cycle progression are two mechanisms that might account for the weak oncogenicity of HBx. "
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    ABSTRACT: The hepatitis B virus (HBV) is a widespread human pathogen that causes liver inflammation, cirrhosis, and hepatocellular carcinoma (HCC). Recent sequencing technologies have refined our knowledge of the genomic landscape and pathogenesis of HCC, but the mechanisms by which HBV exerts its oncogenic role remain controversial. In a prevailing view, inflammation, liver damage, and regeneration may foster the accumulation of genetic and epigenetic defects leading to cancer onset. However, a more direct and specific contribution of the virus is supported by clinical and biological observations. Among genetically heterogeneous HCCs, HBV-related tumors display high genomic instability, which may be attributed to the ability of HBV to integrate its DNA into the host cell genome, provoking chromosomal alterations and insertional mutagenesis of cancer genes. The viral transactivator HBx may also participate in transformation by deregulating diverse cellular machineries. A better understanding of the complex mechanisms linking HBV to HCC will improve prevention and treatment strategies. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor Perspectives in Medicine 02/2015; 5(2). DOI:10.1101/cshperspect.a021444 · 9.47 Impact Factor
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    • "Hepatocellular Carcinoma (HCC) is a common malignancy and a leading cause of death worldwide. Recent epidemiological data have demonstrated that liver cancer incidence has been continuously rising for more than a decade, not only in Asia and Africa but also in North America and Europe (1). The risk factor of HCC has been identified based on epidemi ological studies i.e. chronic HBV and HCV infection and prolonged exposure to alfatoxin (2). "
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    ABSTRACT: The HBV-X (HBX) protein is believed to contribute to the development of HCC. However, the molecular mechanisms involved in HBX- mediated hepatocarcinogenesis remain obscure. In this study, the effect of hepatitis B virus X gene and its protein product HBxAg on expression of p53 gene in Hep G2 cell line was investigated. Viral DNA extracted from HBV-positive serum and HBX gene region was amplified using polymerase chain reaction (PCR). Then, PCR product was cloned into the pcDNA3 vector. After confirmation of cloning, the recombinant plasmid pcDNA3-X was transfected into HepG2 cell line using lipid-mediated DNA-transfection procedure. SDS-PAGE and western blotting methods were used to identify expression of HBX protein. Relative quantification was used to analyze the p53gene expression using the 2-(ΔΔ Ct) method. Recombinant plasmid pcDNA3-HBX was confirmed by restriction endonucleases digestion and colony-PCR. The results of SDS-PAGE and western blot assays showed that HBX gene could be expressed in Hep G2 cell line. There was no significant difference between the expression levels of p53 compared with GAPDH gene as housekeeping gene (p < 0.05). There was no significant difference in the protein levels between the transfected cells with X gene containing HBX130 and HBX131 double mu-tations and p53 gene. It is necessary to do more studies on Hepatitis B virus to understand the role of HBX on the development of liver cancer and its function on p53 tumor suppressor protein.
    12/2014; 6(1):3-9.
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    • "In addition, a conjunction of risk factors is frequent in clinical practice, and the specific impact of each factor in hepatocarcinogenesis is difficult to evaluate. The most clear-cut direct carcinogenic role is that of chronic hepatitis B infection, that can lead to HCC outside of the background of cirrhosis [11]. It includes well known viral integration into the tumour genome, but also the potential oncogenic role of viral protein. "
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    ABSTRACT: Hepatocellular carcinoma is related to various etiologies including hepatitis B, hepatitis C, high alcohol intake, aflatoxin B1 and metabolic syndrom. Most of the time HCC developped on cirrhosis. Consequently, the mechanims of carcinogenesis of these different risk factors are difficult to separate from the events leading to cirrhosis. In contrast, aflatoxin B1 and hepatitis B have a clear direct oncogenic role through point mutations in the TP53 tumor supressor gene and insertionnal mutagenesis respectively. Finally, next-generation sequencing and transcriptome analysis will refine our knowledge of the relationship between etiology and the genetic events that draw the mutationnal landscape of hepatocellular carcinoma.
    Baillière&#x027 s Best Practice and Research in Clinical Gastroenterology 10/2014; 28(5). DOI:10.1016/j.bpg.2014.08.006 · 3.48 Impact Factor
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