Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the applicability of recombinant adenoviral vectors in gene transfer to liver cancers, we infused the recombinant adenoviruses AD5CMV-LacZ and Ad5CMV-p53 through the portal veins into two lines of transgenic mice, one bearing the SV40 T antigen and the other the human hepatitis B viral envelope protein. These transgenic animals develop hepatocellular carcinomas (HCC) with predictable pathological manifestations. The levels of expression of the transgenes were dependent upon the viral doses. In all cases, high levels of expression were detected within 2 or 3 days after infusion, but were drastically reduced 7 days after infusion. Significant toxicities were found in the infused animals: > 80% of them died within 7 days after infusion with 10(10) pfu, and transgenic animals bearing HCC apparently were more sensitive to viral toxicity. Although a lower dose (10(9) pfu/animal) produced less toxicity, the levels of expression were substantially reduced (only about 10% of that in animals infused with 10(10) pfu). When Ad5CMV-p53 was infused into animals with nodular hyperplastic stage, the expression of the reporter gene seemed to distribute preferentially at the peripheries of the tumor nodules, and low levels of transgene expression were seen inside the nodules. In tumors in which necrotic lesions were evident, p53 was also expressed at the perpheries of the lesions. These distribution patterns were seen in both tumor models. There was no apparent suppression of tumor growth in the Ad5CMV-p53-infused animals. Our results suggest that alternative methods for gene therapy for HCC need to be explored.
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PMID:Adenoviral delivery of recombinant DNA into transgenic mice bearing hepatocellular carcinomas. 883 22

Evidence of a tumorigenic potential of the hepatitis C virus (HCV) has so far come mainly from epidemiological data. Longitudinal studies have shown that 16 of 62 anti-HCV antibody (ab)-positive Japanese patients developed hepatocellular carcinoma (HCC) within 5 yr. HCC-related deaths were significantly (p = 0.01) higher in Swedish anti-HCV ab-positive patients than in anti-HCV ab-negative controls (18 vs. 4%). The relative frequency of anti-HCV ab in HCC patients has been reported to be as high as 72% in Spain, 49-62% in Italy and 58% in France. It ranges between 9 and 36% in the USA and is about 26% in Germany. In HBV-endemic areas like South East Asia and Equatorial Africa, HCV-related HCCs play a minor role. The relative risk of developing HCC was elevated (up to 69.1-fold) for anti-HCV ab-positive patients as compared to anti-HCV ab-negative controls in almost all geographic areas studied to date. There is some evidence for an increased risk of developing HCC when hepatitis B virus (HBV) coinfection is present. Cirrhosis is likely to represent an additional risk factor for the development of HCC in anti-HCV ab-positive patients. Blood transfusions are the source of infection in barely one third of anti-HCV ab-positive HCC patients. There seems to be no significant difference in age or gender between anti-HCV ab-positive and ab-negative HCC patients. The additional impact of alcohol consumption and of the HCV genotype is presently under investigation. On the molecular level, HCV replication intermediates have been detected in HCC tissue and point mutations within the p53 gene have been demonstrated. However, the pathomechanism leading to HCV-mediated cell transformation remains unsolved.
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PMID:Hepatitis C virus infection as a major risk factor for hepatocellular carcinoma. 883 91

The hepatitis B virus (HBV) genome encodes a 154 amino acid protein termed X (HBx, hepatitis B x protein), which is a promiscuous transcriptional activator of polymerase II and III promoters. HBx upregulates a wide range of cellular and viral genes and is thought to facilitate viral pregenome and mRNA transcription; however, its precise role in the viral replication cycle remains to be elucidated. The functional mechanisms of HBx appear very complex. It was shown to activate transcription factors AP-1 and NF-kappa B vis cytoplasmic pathways including ras-MAP kinase. In contrast, nuclear HBx is thought to activate the transcriptional machinery directly. A second transcriptional activator protein (Mst, middle s transactivator) is encoded by 3'-truncated preS2/S sequences of integrated HBV DNA, but not by the intact viral gene. HBx and Mst may contribute to the pathogenicity of chronic hepatitis B and are suggested to promote hepatocyte transformation via upregulation of cellular proto-oncogenes. Further, HBx may enhance HBV related carcinogenesis by inactivation of the tumour suppressor gene product p53.
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PMID:Hepatitis B virus transcriptional activators: mechanisms and possible role in oncogenesis. 887 69

Hepatitis B virus (HBV) is a co-factor in some hepatocellular carcinomas (HCC). Chronic infection with HBV is a risk factor for tumor development, suggesting the accumulation of cellular genetic changes. HBV DNA is frequently found integrated at random sites in HCC, with chromosomal deletions and rearrangements being common at the sites of viral integration. Tumor suppressor gene p53 is frequently altered in HCC. Environmental carcinogens are factors in HCC development in certain geographic locations. HBV encodes a protein (X) known to transactivate viral and cellular genes; the X gene is often retained in HCC. To learn more about X gene function. We employed the yeast two-hybrid genetic system to seek X-interactive proteins. A cellular protein, designated XAP-1, was recovered that interacts specifically with the X protein. XAP-1 is the human homologue of the monkey UV-damaged DNA-binding protein (UV-DDB); the UV-DDB protein functions in DNA repair and is defective in some xeroderma pigmentosum group E patients. The interaction between XAP-1 and HBV X protein was confirmed by several independent methods. This suggests that cellular DNA repair processes may be affected by HBV and that the resulting genetic instability may contribute to hepatocellular carcinogenesis. A unifying model of the molecular basis of HBV involvement in HCC development is presented. Fundamental components of the model are chronic infection by HBV and viral effects on cellular DNA repair. This model has implications for the possible role of HCV infection in the induction of HCV-associated HCC.
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PMID:Viral co-factors in liver cancer: lessons from hepatitis B virus. 887 24

The majority of hepatocellular carcinomas (HCCs) from hepatitis B virus (HBV)-endemic areas contain integrated viral sequences. To better understand the role of HBV DNA insertion in tumorigenesis, we examined the integration site of a HCC harboring a single insert. Cellular DNAs flanking the viral sequences were mapped to chromosomes 17 and 8, indicating a translocation had occurred at the site of viral integration. Regional mapping of chromosome 17 demonstrated that HBV had integrated in 17p12-pter, a region that harbors the p53 tumor suppressor gene. Many studies have shown that chromosome 17p allele loss occurs frequently in HCCs from certain geographical areas. To investigate the chromosome 8 allele status in Chinese HCCs, a panel of 37 matched normal and HCC DNAs from Qidong, China was analyzed for tumor-specific allele loss with RFLP probes from both arms of chromosome 8. Tumor-specific loss of heterozygosity was highest on the short arm with 71.4% (10/14) and 85.0% (17/20) of the informative patients missing an allele for 8p23 (YNM3) or 8p21 (NEFL), respectively. Allele loss from the long arm of chromosome 8 was also observed with 30.0% (6/20) and 33.3% (7/21) of the samples informative for 8q22 (CA2) and 8q24 (MCT128.2), respectively. The high allele loss on 8p correlates with recent studies of other human cancers and is interpreted to indicate that a tumor suppressor gene(s) whose loss is important for carcinogenesis lies within this region. These findings also support a model in which HBV insertions associated with gross chromosomal changes can identify genomic regions where alteration is important for development of some HCCs.
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PMID:Frequent loss of chromosome 8p in hepatitis B virus-positive hepatocellular carcinomas from China. 889 69

Chronic infection with hepatitis B virus (HBV) is associated with the development of human hepatocellular carcinoma (HCC). One of the HBV genes, HBx, may have transforming potential, but this issue is still the subject of controversy. One of the major difficulties in addressing this question is the lack of a suitable in vitro model. We used a nontransformed, differentiated murine hepatocyte cell line (AML12) to transfect the HBx gene and examine its transforming capabilities. Because mutations of the p53 gene, in particular at codon 249, have been implicated in HCC development in geographical areas with high incidence of the tumor, we also studied the putative cooperative role in transformation between HBx and mutated p53 by cotransfecting HBx with a murine p53 mutant equivalent to human ser249 (ser246p53). Transfection with HBx plasmids containing the HBx gene under the control of two different promoters resulted in fewer colonies than in control plasmids. The toxic effect of HBx on colony formation was abolished by cotransfection with 246p53, suggesting that the inhibitory effect requires functionally intact p53. Clonal cell lines that stably expressed HBx messenger RNA (mRNA) (HBX lines) were tested for their growth characteristics and their ability to grow in soft agar and form tumors in nude mice. At passages 19-27 after transfection, one of four HBx-expressing lines showed the capacity for anchorage-independent growth in soft agar and produced poorly differentiated hepatocellular carcinomas in 8 of 13 sites of injection in nude mice. HBX lines as well as clonal cell lines of cells transfected with 246p53 (246 cell lines), cotransfected with HBx and 246p53 (246x lines) or transfected with control plasmids, were analyzed by flow cytometry to determine the fraction of cells in S phase (SPF). 246 and 246X lines had similar SPFs that were approximately twofold greater than control or HBX lines. 246x lines showed morphological changes in culture such as marked cellular heterogeneity, cell crowding, and the presence of multinucleated giant cells, but their tumorigenicity was not increased compared with the HBX lines. These data show that HBx has a weak tumorigenicity in murine hepatocytes and that the addition of mutation of p53 at codon 249 to HBx expression does not increase tumorigenicity in AML12 cells.
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PMID:Analysis of the tumorigenicity of the X gene of hepatitis B virus in a nontransformed hepatocyte cell line and the effects of cotransfection with a murine p53 mutant equivalent to human codon 249. 890 70

Infection with hepadnaviruses and exposure to aflatoxin B1 (AFB1) are considered major risk factors in the development of hepatocellular carcinoma (HCC) in humans and in animals. A high rate of mutations in the p53 tumor suppressor gene in hepatocellular carcinomas of predominantly hepatitis B virus (HBV) carrier patients has been recently related to dietary aflatoxin. Another member of the hepadnavirus family, the woodchuck hepatitis virus (WHV), infects woodchucks in a manner similar to that of HBV in humans. Therefore, it was of particular interest to determine whether the p53 gene in woodchuck HCCs associated with hepadnavirus infection and with exposure to AFB1 is affected in the same manner as in human HCCs. By direct PCR-sequencing, we analyzed exons 4-9 of the p53 gene in 13 HCCs from 12 woodchucks (two uninfected, ten WHV carriers). Six WHV carrier and two uninfected woodchucks were treated with AFB1. None of the analyzed HCC samples exhibited mutations, either in p53 gene exons 4-9, or in splicing donor-acceptor sites. The present data are consistent with our previous study that indicated a low rate of p53 mutations in HCCs of AFB1-treated ground squirrels, either infected or not infected with ground squirrel hepatitis virus, and in WHV carrier woodchucks not exposed to AFB1. Overall, our findings indicate that in woodchucks and in ground squirrels exposure to aflatoxin may affect the development of p53 mutations less than in humans.
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PMID:Absence of mutations in the p53 tumor suppressor gene in woodchuck hepatocellular carcinomas associated with hepadnavirus infection and intake of aflatoxin B1. 900 7

Inactivation of the tumor suppressor p53 seems to be important to the pathogenesis of hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus infection. Although this inactivation may be due to mutations in the p53 gene, recent evidence suggests that the hepatitis B virus-encoded X antigen (HBxAg) binds to and inactivates wild-type p53. Hence, experiments were designed to test the hypothesis that there is a low frequency of p53 mutations in HBxAg-positive HCC. HBxAg and p53 were assayed by immunohistochemistry (IHC) in HCC and nontumor liver from 16 Chinese patients, half of whom were hepatitis B surface antigen carriers. HBxAg was detectable in tumor and/or nontumor cells from all patients by IHC; six of these samples also had detectable p53. To determine whether p53 detection by IHC, and hence stabilization, is associated with mutation, sequencing of p53 exons 5-8 was performed with each patient sample. Wild-type sequences were found in 13 of 16 HBxAg-positive cases (81%). Hence, HBxAg is a common marker of HCC that correlates with the persistence of wild-type p53 among both carriers and noncarriers. The low frequency of p53 mutations in HCC in these patients implies that p53 inactivation may occur predominantly by complex formation with HBxAg.
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PMID:Integrity of p53 in hepatitis B x antigen-positive and -negative hepatocellular carcinomas. 901 69

Chronic infection with hepatitis B virus is associated with a high incidence of liver diseases, including hepatocellular carcinoma. Hepatitis-B-virus-encoded X antigen (HBxAg) stimulates virus gene expression and replication, which may be important for the establishment and maintenance of the chronic carrier state. Integration of viral DNA encoding HBxAg during chronic infection results in increased X antigen expression. HBxAg overexpression may alter signal transduction pathways important for the regulation of cell growth during hepatocellular regeneration. The finding that HBxAg binds to and inactivates negative growth-regulatory molecules, such as the tumor suppressor p53, suggests additional ways that HBxAg may act in hepatocarcinogenesis. HBxAg may also stimulate the expression of positive growth regulators, such as insulin-like growth factor II and the insulin-like growth factor I receptor. The finding that HBxAg may compromise DNA repair and that it may effect the normal turnover of growth-regulatory molecules in the proteasome may also contribute to its carcinogenic properties. Hence, HBxAg may contribute to the pathogenesis of chronic infection and development of hepatocellular carcinoma in a variety of ways.
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PMID:Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. 909 70

Localization of p53 oncoprotein was investigated in 60 hepatocellular carcinomas (HCCs) from patients resident in the Northwest and Central Greece. The streptavidin-biotin complex immunoperoxidase method was performed in archival formalin-fixed, paraffin-embedded material, using the monoclonal antibody DO-1. The aim of our study was to correlate p53 expression with histological and epidemiological data. p53 overexpression in patients with serological hepatitis B or C was greater (47%) as compared to that observed in patients without these markers (p < 0.01). Morphologically normal liver tissue (NLT) and liver cell dysplasia (LCD) was recognized adjacent to HCC developing on non-alcoholic cirrhotic livers in patients with "NonA, NonB hepatitis" from between 1975-1986. NLT and LCD and p53 oncoprotein was expressed in 10% of the cases. No relationship was observed between p53 expression and tumor histological grade, patients' age and sex. These results suggest that in Northwest and Central Greece, p53 oncosupressor gene may be involved in some HCCs; it may be associated with viral chronic infection disease (HBV or HCV), and as yet with uncharacterized viruses which remain to be determined.
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PMID:p53 expression in hepatocellular carcinoma in Greece. Correlation with epidemiological and histopathological data. 912 28


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