Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the major debates in hepatocellular carcinogenesis at present is whether the hepatitis-B and -C viruses are directly carcinogenic or exert their effect indirectly by causing chronic necro-inflammatory hepatic disease, which in turn is responsible for malignant transformation of hepatocytes. This debate has been fueled by the observation that hepatitis C virus is a single-stranded RNA virus with no precedent for inducing cancer but with a marked propensity to cause chronic necro-inflammatory hepatic disease and by the findings in Chisari's transgenic mouse model, which suggest that severe and prolonged hepatocellular injury per se induces a proliferative response that progresses to tumour formation. Recent reports of a guanine to thymine mutation of the third base of codon 249 of the tumour suppressor gene, p53, in 50% of patients with hepatocellular carcinoma in regions of high aflatoxin exposure, and mutagenic experiments showing that aflatoxin B1 binds particularly to guanine residues in G-C-rich domains and that codon 249 is a preferred target have suggested a mechanism whereby aflatoxin might induce malignant transformation.
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PMID:Tumours of the liver. 133 85

The products of the two major suppressor genes p53 and Rb interact with the oncogene products of the DNA tumour viruses. These viral-host protein interactions mimic and interfere with the normal interactions of p53 and Rb with host proteins. The Rb gene product is frequently mutated in human cancers such that it no longer binds to viral or host proteins. In contrast we find that this is not the case with p53 as some, but not all, mutant p53 proteins still bind to the SV40 T antigen. In particular the hot spot mutation found in most Chinese and African cases of hepatocellular carcinoma (HCC) retains T binding activity. The simple subdivision of different p53 mutations revealed by this analysis may have diagnostic and prognostic consequences.
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PMID:Diversity of human p53 mutants revealed by complex formation to SV40 T antigen. 133 35

Human hepatocellular carcinomas from patients in Britain, an area of low prevalence of hepatocellular carcinoma and low dietary exposure to aflatoxin B1, were analyzed for mutations in the p53 tumor-suppressor gene. Abnormalities in the p53 gene were detected in 2 of 19 hepatocellular carcinomas by polymerase chain reaction--single-stranded conformation polymorphism. Direct sequencing of the evolutionarily conserved regions of p53 (exons 5, 6, 7 and 8), where mutations have been commonly found in a variety of tumors, confirmed that only two hepatocellular carcinomas had mutations in p53, one a 6-bp deletion of codons 158 and 159 (exon 5) and the other a G to A transition at codon 286 (exon 8). No mutations were found in any hepatocellular carcinoma in exons 6 and 7; in particular all tumors had wild-type sequence at codon 249, which has been reported to be a mutational hot spot in the p53 gene in hepatocellular carcinomas from high incidence areas such as China and southern Africa. Abnormalities in p53 expression were examined by immunohistochemistry and found in 1 of the 19 hepatocellular carcinomas. These findings show that p53 mutations are infrequently involved in the malignant transformation of hepatocytes in an area of low hepatocellular carcinoma prevalence. They support the suggestion of a possible link between dietary exposure to aflatoxin and selective G to T mutations at codon 249 of the p53 gene. Our observations also indicate that hepatitis B virus infection alone, present in six of the hepatocellular carcinomas examined, does not account for the specificity for codon 249 mutations reported from endemic areas.
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PMID:Analysis of the p53 tumor-suppressor gene in hepatocellular carcinomas from Britain. 133 21

The expression of nine oncogenes (c-myc, N-myc, N-ras, H-ras, k-ras, abl, fos, src, and raf) and two tumor suppressor genes (p53 and RB) were studied by northern blot hybridization in six human hepatocellular carcinoma or hepatoblastoma cell lines (PLC/PRF/5, Hep3B, Hep G2, 2.2.15, HLE, and HLF) and in a human embryonic lung fibroblast cell line (WI-38) to look for differences that might be associated with the presence (PLC/PRF/5, Hep3B, and 2.2.15) or absence (Hep G2, HLE, and HLF) of integrated hepatitis B virus (HBV) DNA. The levels of expression of the oncogenes and tumor suppressor genes were unrelated to the presence or absence of integrated HBV-DNA. Furthermore, the intensity of expression of these oncogenes was no greater in the 2.2.15 cell line (consisting of Hep G2 cells transfected with hepatitis B virus) than in untransfected Hep G2 cells.
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PMID:Expression of oncogenes and tumor suppressor genes in human hepatocellular carcinoma and hepatoblastoma cell lines. 133 79

Rat hepatocellular carcinomas (HCCs) induced by aflatoxin B1 (AFB) treatment were examined for changes in the p53 tumor suppressor gene and in p53 suppressor gene expression. A high proportion of HCCs (nine of 11 tumors in six of eight animals) exhibited new p53 restriction fragments, indicating genomic alterations of one of the p53 alleles. Each tumor with an altered p53 restriction-fragment pattern exhibited a new fragment in one of two size classes (3 kb or 7 kb with EcoRI digestion) that were missing portions of the 3' end of the p53 gene. These findings indicate that apparently similar genomic rearrangements or deletions occurred independently in AFB-induced tumors. When compared with nontumor liver tissue from the same animal, the tumors with p53 gene alterations showed dramatically reduced levels of p53 mRNA and protein and greatly increased levels of histone H2B and retinoblastoma tumor suppressor (Rb) mRNA. In two HCCs showing no evidence of p53 restriction-fragment alterations, mutant p53 protein was detected. Mutant protein was also detected in two liver samples containing an adenoma and altered foci. These data suggest that alterations of the p53 tumor suppressor gene are involved in the induction of rat HCC by AFB.
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PMID:Alterations in the structural gene and the expression of p53 in rat liver tumors induced by aflatoxin B1. 135 44

Mutations in the p53 gene are frequent genetic alterations in human hepatocellular carcinomas. We have examined, by single-strand conformation polymorphism analysis of polymerase chain reaction products, a total of 93 carcinogen-induced liver tumors from mice of three different strains (C3H/He, C57BL/6J, and B6C3F1) for the presence of p53 aberrations. Hepatoma lines, established from 12 liver tumors, were also included in the analysis. While structural aberrations of the p53 gene were not detected in any of the primary mouse liver tumors analyzed, single-base substitutions occurred at different locations within the p53 gene in three of the cell lines during in vitro propagation. One hepatoma line carried two point mutations on separate alleles. All four mutations were either G:C----C:G or C:G----G:C transversions. Mutations at codon 61 of the c-Ha-ras gene, which were frequent in primary liver tumors from C3H/He and B6C3F1 mice, were not detected in the hepatoma lines. Our data indicate (i) that c-Ha-ras but not p53 mutations play an important role during the early stages of mouse hepatocarcinogenesis and (ii) that p53 mutations confer a selective growth advantage to the mutated hepatoma cells in vitro.
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PMID:p53 mutations are absent from carcinogen-induced mouse liver tumors but occur in cell lines established from these tumors. 138 43

Teleocidin, a tumor promoter, inhibited the proliferation, enhanced cytokeratin assembly and increased the type III procollagen production of PLC/PRF/5 hepatoma cells. Teleocidin transiently increased the levels of c-fos and p53 mRNAs measured by reverse transcription and polymerase chain reaction. This was followed by a reduction of c-myc mRNA and an increase of cytokeratin mRNA. The level of p120 mRNA was not remarkably altered. Sequential alterations of the expression of c-fos, p53, c-myc and cytokeratin genes induced by teleocidin may be responsible for the morphological and functional changes of hepatoma cells induced by this tumor promoter.
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PMID:Co-ordinate expression of c-fos, p53 and cytokeratin genes during the alteration of growth of human hepatoma cells. mRNA levels measured by reverse transcription and polymerase chain reaction. 138 34

For colorectal carcinomas, the rate of tumor development is proportional to the fourth to sixth power of elapsed time, suggesting that four to six independent events are necessary. Although similar calculations have not been made for HBV-associated HCCs, it is likely that this is also the case for HCCs, since individuals with persistent HBV infection do not usually develop HCC until they are 45 or greater years old. As evidence for specific genetic and epigenetic changes in HCCs accumulate, the important players in multistep hepatocarcinogenesis are becoming clearer. However, even though Myc family oncogenes are clearly implicated in woodchuck HCC, similar integrations have not been found in human HCCs. Therefore, although rodent and human systems have many similarities, we must realize that important differences may also exist. Regarding tumor suppressor genes, the evidence for p53 alterations in HCC is strong. A growing body of evidence suggests further that alterations in the retinoblastoma gene and one or more tumor suppressor genes on chromosome 11 are also involved in HCC. HBV integrations may certainly play a role in the generation of chromosome aberrations leading to loss of tumor suppressor alleles, since chromosomes 11 and 17 are the most common integration sites. Finally, the role of X proteins as participants in malignant transformation has been demonstrated for certain immortalized, nontransformed hepatocytes. Altered autocrine mechanisms of cell growth control, possibly involving IGF-II, are clearly implicated in HCC. Paracrine mechanisms for the control of hepatocyte growth and differentiated functions may also be altered as a result of the synthesis and secretion of a complex array of interleukins, HGF, and basic and acidic FGFs by cells in the inflammatory and cirrhotic lesions of precancerous livers. Whether the order of molecular changes in the hepatocyte is important for malignant progression is presently not clear. What is clear, however, is that hepatocarcinogenesis involves alterations in the concerted action of protooncogenes, growth factor, and tumor suppressor genes. How these factors interact will provide a more complete understanding of the mechanism or mechanisms of hepatic oncogenesis.
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PMID:Cellular and molecular mechanisms of hepatocarcinogenesis. 143 79

Abnormalities of the p53 gene have been identified in many malignancies, with reports of aberration in over half of colorectal, lung, breast and hepatocellular carcinoma cases. The normal gene acts as a recessive oncogene, while mutations change the apparent function to that of a dominant oncogene. In this investigation a 3-layered immunoperoxidase technique was applied to routinely fixed and paraffin-embedded tissue sections from 125 gastric carcinomas, using a polyclonal anti-p53 antibody (CM-I). We found that 57% of these carcinomas expressed high levels of p53 protein (positive nuclear staining). Survival analysis revealed a strong association between p53 status of the tumour and patient survival time after diagnosis (p = 0.02, Mantel-Cox Test); odds ratio of death, 2.09 (95% confidence interval 1.02 to 4.25). The 5-year survival of patients with p53-expressing tumours was 24%, compared with 56% for those non-p53-expressing tumours (the median survival times were 13 and 102 months, respectively).
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PMID:p53 expression and prognosis in gastric carcinoma. 155 84

The development of hepatocellular carcinoma (HCC) presumably occurs in multiple steps and is influenced by numerous factors. Hepatitis B virus (HBV) is strongly associated with the development of HCC in people chronically infected with the virus, but the mechanism of viral involvement remains unclear. One possibility is that the gross chromosomal alterations frequently observed in HCC DNA at the site of HBV integration may alter the expression of important nearby cellular genes. We previously reported the cloning and characterization of a HBV insert from a Chinese HCC. The viral insert mapped to chromosome 17p11.2-12, and cellular sequences were duplicated at the site of viral integration. In the present study a DNA probe derived from cellular DNA sequences adjacent to the previously characterized HBV insert was used to analyze a set of 19 matched normal liver and HBV-positive hepatoma samples obtained from the same region of China, near Shanghai. Tumor-specific DNA changes were detected in two additional HCCs, suggesting that the small region of chromosome 17p defined by the flanking cell DNA probe is commonly altered in hepatomas. Restriction fragment length polymorphism studies demonstrated that the loss of one copy of portions of chromosome 17 occurred in 10 (53%) of the 19 patients. The loss of one allele of the p53 gene (located on chromosome 17p13) occurred in at least 6 (60%) of the 10 patients who were heterozygous at the p53 locus. As the p53 gene is known to possess tumor suppressor activity, the functional loss of this gene may be a significant step in the development of a subset of HCCs. High levels of allele loss also were detected for chromosomes 8q (4 of 9; 44%) and 16p (5 of 6; 83%) and may indicate the presence of additional cellular genes whose functional loss is important in the development of HCCs.
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PMID:Hepatitis B virus integration event in human chromosome 17p near the p53 gene identifies the region of the chromosome commonly deleted in virus-positive hepatocellular carcinomas. 167 Sep 94


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