Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experiments were done to show whether a G to T mis-sense mutation at the third base of codon 249 of the p53 tumour suppressor gene is a 'hot spot' of aflatoxin attack as suggested by the results of epidemiological studies. Liver tissue from liver cancer patients in Taiwan and Japan was analysed for the presence of aflatoxin-DNA adducts (ADA) as a marker for aflatoxin exposure and an AGG to AGT transversion at codon 249 of the p53 gene. Ten per cent of samples containing ADA, indicating definite exposure of the subjects to aflatoxin, was found to harbour the codon 249 mutation, whereas 18% of the samples with no detectable adducts also contained the mutation. Our data do not support the hypothesis that codon 249 of the p53 gene DNA is a hot spot for aflatoxin mutagenesis as a 'late stage event' in human hepatocellular carcinogenesis.
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PMID:Recent aflatoxin exposure and mutation at codon 249 of the human p53 gene: lack of association. 766 37

To examine the significance of mutation of the p53 tumour suppressor gene in the development of human hepatocellular carcinoma in a high-prevalence area for hepatitis B viral infection but a low-exposure area for aflatoxin B1, the spectrum of p53 gene mutations was examined in 21 tumour samples from Hong Kong Chinese patients, all of whom were HBsAg positive. DNA sequencing covering exons 5 to 9 of the p53 gene and Hae III restriction enzyme digestion for preliminary assessment of mutation at codon 249 were performed. Immunohistochemical staining with anti-p53 monoclonal antibodies was done on both tumour and nontumour liver tissues. Six tumours (28.6%) showed a p53 mutation and all were point mutations. Of the six point mutations, two (9.5%) were at codon 249 and both were G to T transversions (AGG-->ATG and AGG-->AGT transversions). The remaining point mutations were transversions scattered at codon 172 (exon 5), 214 (exon 6), 273 (exon 8) and 330 (exon 9). Mutated p53 protein was detected in five of these six cases with demonstrable point mutations by DNA sequencing, in contrast to none detected in all of the 15 cases without demonstrable point mutations. The presence of p53 mutations, including those at codon 249, did not show a significant association with tumour size, sex, age, tumour invasiveness in terms of liver invasion, microsatellites and venous permeation, cirrhosis and encapsulation, but tumours with low cellular differentiation tended to have a higher incidence (71%) of point mutations than those with high cellular differentiation (8%). In conclusion, both the overall p53 mutation rate and that a codon 249 in HCC in Hong Kong Chinese are lower than those reported in tumours from China and sub-Saharan Africa. The low mutation rate at codon 249 is compatible with a low aflatoxin exposure. A special type of p53 mutation has not been found to be associated with hepatitis B viral infection. Mutations of p53 gene tends to occur in tumours with low cellular differentiation, suggesting a late occurrence in the event of tumour progression.
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PMID:p53 gene mutation spectrum in hepatocellular carcinomas in Hong Kong Chinese. 810 45

TP53 gene mutations occur in 30 to 55% hepatocellular carcinomas. Both the frequency and the type of p53 mutations in HCC vary according to geographical location of tumors. A specific mutation at codon 249 (AGG-->AGT) was found at high frequency in tumors from high aflatoxin-areas. TP53 mutations in other geographic locations are less frequent and scattered on the exons encoding the central region of the protein. TP53 mutations observed in hepatocellular carcinoma are accompanied by a loss of wild-type p53 function. Moreover, the p53-249ser mutant appears to display a gain of function at some degree. In addition to p53 inactivation by gene mutation, there is growing evidence that the wild-type p53 functions can be inactivated by the HBx protein of Hepatitis B Virus. The hepatocellular functions of wild-type p53 protein are not entirely known. The present data suggest that the DNA damaging agents induce p53-dependent cell cycle arrest or apoptosis in cell lines derived from normal liver or hepatocellular carcinoma. In contrast, the exposure of mice to genotoxic agents does not induce p53-dependent changes in normal adult liver. This could be due to the fact that the hepatocytes of the adult liver are quiescent cells.
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PMID:TP53 and hepatocellular carcinoma. 976 50

Hemochromatosis and Wilson disease (WD), characterized by the excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, we have determined the frequency of p53 mutated alleles in nontumorous liver tissue from WD and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249 (P < 0.001) and C:G to A:T transversions and C:G to T:A transitions at codon 250 (P < 0.001 and P < 0.005) were found in liver tissue from WD cases, and a higher frequency of G:C to T:A transversions at codon 249 (P < 0.05) also was found in liver tissue from hemochromatosis cases. Sixty percent of the WD and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggests nitric oxide as a source of increased oxidative stress. A high level of etheno-DNA adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochromatosis patients has been reported previously. Therefore, we exposed a wild-type p53 TK-6 lymphoblastoid cell line to 4-hydroxynonenal, an unsaturated aldehyde involved in lipid peroxidation, and observed an increase in G to T transversions at p53 codon 249 (AGG to AGT). These results are consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene.
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PMID:Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases. 1105 Jan 62

Angiotensinogen, a member of the serpin family, is involved in the suppression of tumor growth and metastasis. To investigate whether human angiotensinogen protects against tumor progression in vivo, we established an original bitransgenic model in which transgenic mice expressing human angiotensinogen (Hu-AGT-TG mice) were crossed with a transgenic mouse model of hepatocellular carcinoma (HCC-TG mice). Bitransgenic mice overexpressing human angiotensinogen (HCC/Hu-AGT-TG) had a significantly longer survival time than the HCC-TG mice and a reduction of both tumor growth and blood flow velocities in the liver. This antitumor effect of angiotensinogen is related to a reduced angiogenesis, impaired expression of endothelial arterial markers (active Notch4, Delta-like 4 ligand, and ephrin B2) with a decrease of arterial vessel density in HCC/Hu-AGT-TG mice liver. Overexpression of human angiotensinogen decreases angiogenesis, and prevents tumor sinusoids from remodeling and arterialization, thus delaying tumor progression in vivo.
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PMID:Angiotensinogen delays angiogenesis and tumor growth of hepatocarcinoma in transgenic mice. 1931 81