Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma

Wang, Jian; Chenivesse, Xavier; Henglein, Berthold; Bréchot, Christian

doi:10.1038/343555a0

Cited by 632 publications

(296 citation statements)

References 38 publications

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“…The caveat to this putative role is whether cyclins are acting as proto-oncogenes resulting in inappropriate expression in tumours. This is clearly the case for cyclin D1 (Hall and Peters, 1996) and a similar role has been suggested in some studies for cyclin A (Furihata et al, 1996;Wang et al, 1990).…”

supporting

confidence: 79%

Aberrant expression of cyclin A in head and neck cancer

et al. 2000

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Cyclin A expression was studied in a series of 65 squamous cell carcinomas of the head and neck (HNSCC) and compared with known markers of proliferation, iododeoxyuridine (IdUrd) and Ki-67, to assess whether aberrant expression was prevalent. Patients had previously been administered IdUrd to study cell kinetics in relation to outcome of radiotherapy. The data showed that all three parameters were highly correlated although the absolute values were different. The median labelling indices (LI) for IdUrd, cyclin A and Ki-67 were 10.7, 17.1 and 30.8% respectively, reflecting the known pattern of differential cell cycle expression. However, there were a significant number of cases in which an unexpected relationship between cyclin A and either IdUrd or Ki-67 was present. Some of these were attributable to overexpression but others indicated underexpression. Although the greater variability and range of cyclin A expression, coupled with its more closely associated role in cell cycle regulation, might suggest that it may be a more informative marker for cell proliferation than Ki-67, the aberrant expression seen in over one third of cases would indicate that caution should be exercised in interpreting cyclin A as a surrogate marker of proliferation in HNSCC. © 2000 Cancer Research Campaign

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supporting

confidence: 79%

Aberrant expression of cyclin A in head and neck cancer

et al. 2000

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“…First, integration of the viral DNA in the host genome can induce chromosome instability (Aoki et al, 1996). Second, insertional mutations have been described in which HBV integration at specific sites activates endogenous genes such as retinoic acid b-receptor (Dejean et al, 1986), cyclin A (Wang et al, 1990) and mevalonate kinase (Graef et al, 1994). More recently, 15 new genes were found to be altered by an HBV integration in tumors, suggesting that viral integration in the vicinity of genes controlling cell proliferation, viability and differentiation is a mechanism frequently involved in HBV hepatocarcinogenesis (Ferber et al, 2003;Horikawa and Barrett, 2003;Paterlini-Brechot et al, 2003).…”

Section: Genetic Alterations and Hepatitis B Virus Infectionmentioning

confidence: 99%

Genetics of hepatocellular tumors

2006

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Numerous genetic alterations are accumulated during the process of hepatocarcinogenesis. These genetic alterations can be divided into two groups. The first set of genetic alterations is specific of hepatocellular tumor risk factors. It includes integration of hepatitis B virus (HBV) DNA, R249S TP53 (tumor protein p53) mutation in aflatoxin B1-exposed patients, KRAS mutations related to vinyl chloride exposure, hepatocyte nuclear factor 1a (HNF1a) mutations associated to hepatocellular adenomas and adenomatosis polyposis coli (APC) germline mutations predisposing to hepatoblastomas. The second set of genetic alterations are etiological nonspecific, it includes recurrent gains and losses of chromosomes, alteration of TP53 gene, activation of WNT/b-catenin pathway through CTNNB1/b-catenin and AXIN (axis inhibition protein) mutations, inactivation of retinoblastoma and IGF2R (insulin-like growth factor 2 receptor) pathways through inactivation of RB1 (retinoblastoma 1), P16 and IGF2R. Comprehensive analyses of these genetic alterations have defined two pathways of hepatocarcinogenesis according to the presence or the absence of chromosomal instability. Hepatitis B virus and poorly differentiated tumors are related to chromosome instable tumors associated with frequent TP53 mutations, whereas non-HBV and well-differentiated tumors are related to chromosomal stable samples that are frequently b-catenin activated. These classifications have clinical relevance as genetic alterations may also be related to prognosis.

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“…The long latency period of tumor development strongly argues against acute oncogenic e ects of HBV. Integration of HBV DNA into the host genome has been detected in most HBVassociated HCCs, but reported cases of direct insertional activation of cellular genes remain extremely rare (Dejean et al, 1986;Wang et al, 1990). It has been proposed that chronic liver damage and compensatory regeneration induced by the host immune response and by long-term expression of viral genes might favor the accumulation of genetic defects (Chisari et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro

et al. 1998

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The hepatitis B virus protein HBx is a promiscuous transactivator implicated in both cell growth and death and in the development of hepatocellular carcinoma. We recently reported that HBx can potentiate c-myc-induced liver oncogenesis in a transgenic model where low level expression of HBx induces no pathology. To assess if HBx could a ect the hepatocyte turnover, we investigated the HBx-elicited apoptotic responses in transgenic livers and in primary hepatocyte cultures. Here we show that transgenic expression of HBx is associated with a twofold increase of spontaneous cell death in the mouse liver. The ®nding that apoptosis was enhanced to similar extents in HBx mice carrying homozygous p53 null mutations implied that functionally intact p53 was not required to transduce the death signal. A direct, dosedependent apoptotic function of HBx was demonstrated in transient transfections of liver-derived cell lines. We further show that stable expression of HBx at low, presumably physiological levels in primary hepatocytes, induced cellular susceptibility to diverse apoptotic insults, including growth factor deprivation, treatment with antiFas antibodies or doxorubicine and oxidative stress. HBx expression, but not p53 status profoundly a ected the commitment of cells to die upon apoptotic stimuli. These data strengthen the notion that HBX may contribute to HBV pathogenesis by enhancing apoptotic death in the chronically infected liver.

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Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma

Cited by 632 publications

References 38 publications

Aberrant expression of cyclin A in head and neck cancer

Aberrant expression of cyclin A in head and neck cancer

Genetics of hepatocellular tumors

p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro

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