Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of tumor suppressor genes is involved in the mechanism of tumorigenesis of many solid tumors. We tested 9 hepatitis B virus (HBV)-positive and 10 HBV-negative hepatocellular carcinomas for loss of somatic heterozygosity using 14 polymorphic probes mapping to chromosomes 4, 11, 13, and 17. Losses were found on all chromosome arms tested. The highest frequency of loss was observed at the D13S1 locus (67%) at band 13q12. Losses were also observed at three other loci on 13q. Twenty-one % of informative cases showed loss on 17p using the probe pYNZ22 which maps near the p53 locus. Losses on 4q were infrequent with 17% found at one locus and no loss at two others. The retinoblastoma gene and the locus on 17p were only inactivated in our HBV-negative tumors, although the numbers were too small for statistical significance. For all loci tested, we found no significant differences in the frequency of losses with HBV status, ethnic background, cirrhosis, grade of tumor, or presence of hemochromatosis.
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PMID:Loss of somatic heterozygosity in hepatocellular carcinoma. 167 14

Hepatocellular carcinoma (HCC) is among the 10 most common tumors in the world. However, incidence is not evenly distributed across the world. In many instances, the proximate cause for the tumor can be identified. Chronic hepatitis B infection is probably the most common cause, followed by chronic hepatitis C. Other important causes are alcoholic liver disease, hemochromatosis, alpha 1-antitrypsin deficiency, and other chronic liver diseases. Although proximate causes may be identifiable, pathogenesis remains uncertain. Factors that may be important include the presence of Aflatoxin B1 in food, genetic changes induced by the hepatitis B virus, and repeated rounds of necrosis and regeneration, also induced by hepatitis viruses. The genes involved and the mutations necessary for hepatic carcinogenesis are unknown, with the sole exception of the p53 gene, which is probably a late phenomenon. Screening for HCC is widely practiced despite the lack of evidence of improved survival. The screening tests used include alphafetoprotein levels and ultrasonography. Screening can identify small tumors; however, survival may not be improved, because the presence of cirrhosis may limit the number of patients who can undergo resections; recurrences or second primary tumors are common; and the presence of chronic liver disease means that survival may be limited anyway. There are many different forms of therapy available; unfortunately, most have not been compared in randomized controlled trials. Surgery remains the therapy of choice if feasible. All other therapy is palliative, including chemotherapy, chemoembolization, hepatic artery embolization, various forms of radiotherapy, and various forms of ablative therapy.
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PMID:Hepatocellular carcinoma. 753 16

Oxyradical overload disease develops in conditions involving chronic inflammation and may be of inherited etiology, e.g. haemochromatosis and Wilson disease, be acquired, e.g. infection with hepatitis B or C virus or Helicobactor pylori, or be chemically induced, e.g. acid reflux in Barrett oesophagus. Susceptibility to cancer is frequently a pathological consequence of extensive oxyradical damage that leads to a cycle of cell death and regeneration and causes mutations in cancer-related genes. In this brief review, we focus on the possible interactive effects of nitric oxide and the p53 tumour suppressor gene in human carcinogenesis.
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PMID:Cancer-prone oxyradical overload disease. 1062 29

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

Hepatocellular carcinoma (HCC) is the most common malignant tumor of males in the world, with an incidence of 1,000,000 new cases a year. It is endemic in Southeast Asia and Sub-Saharan Africa. Risk factors include chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), Aflatoxin B1 uptake, hemochromatosis, and alpha1 -antitripsin deficiency. Epidemiological studies provide evidence for the association of HCC with HBV infection. The incidence of HCC is high in regions hyperendemic for HBV. Chronic carrier state and maternal-infant transmission are important factors in the development of HCC. Evidence of direct oncogenic effect of H BV is well established, HCCs contain viral DNA sequences integrated into hepatocyte DNA that act as random insertional mutagens, and these sites are near genes involved in the control of proliferation and differentiation. The mechanism of hepatitis C virus in hepatocarcinogenesis is still imprecise but a high percentage of cases are related to this virus. Chronic alcohol consumption and cirrhosis are cofactors that increase the development of HCC in patients with chronic viral infection. In experimental carcinogenesis a multipotential element called oval cell proliferates in the early stages. The cellular events are accompanied by increased expression of several growth factors that enhance the survival of carcinogen-activated cells by suppressing apoptosis and increasing elements entering the cell cycle. Hepatic carcinogenesis is a complex process associated with accumulation of genetic and epigenetic changes that run through steps of initiation, promotion and progression. Activation of oncogenes of the "ras" family and others has been detected during chemically-induced HCC in rodents, but there is little evidence of such activation in human tumors. The role of tumor supressor genes such as retinoblastoma (RB) and P53 genes has been documented. Aflatoxin B1 that contaminates foods in endemic areas has a clear role in hepatocarcinogenesis. Metabolites of this toxin promote apurinic sites and G to T mutations in chromosomal DNA, the third base of codon 249 of the P53 gene is preferentially targeted to form aducts with aflatoxin B1, and this mutation has been specifically identified in HBV infection. Histological and cytological criteria for the diagnosis of HCC are well established and are based in architectural and cytological changes. An important issue is the diagnosis of liver "nodules" detected by image, from which small biopsies or aspiration material is obtained. Special studies such as reticulin, CD34, cytokeratin profile, and MOC-31 can be very useful for the differential diagnosis of primary and metastatic tumors. Telomerase activity has been found in HCC and negative in pericancerous tissue. It is more pronounced in poorly differentiated tumors and correlates with factors of clinical importance, such as prognosis and recurrences. Cells of well-differentiated HCC have an ultrastructural appearance similar to normal hepatocytes. During the process of dedifferentiation, there is progressive loss of organization of intracellular organelles. The cell cohesion is lost, intercellular gaps with microvilli appear, the sinusoids become capillarized, and reparative changes are seen in the spaces of Disse. A variety of inclusions, such as Mallory bodies, granular material, secondary lysosomes, and Dubin-Johnson pigment, have been described. Fibrolamellar carcinoma has a characteristic histological picture and ultrastructurally oncocytic features. Neuroendocrine granules and combination of HCC with bile duct carcinoma are seen by electron microscopy.
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PMID:Hepatocellular carcinoma: an update. 1178 14

Hepatocellular carcinoma (HCC) accounts for 80-90% of liver cancers and is one of the most frequent carcinomas throughout the world. The disease is more prevalent in parts of Africa and Asia than in North and South America and Europe, with a strong etiological association with viral hepatitis, hemochromatosis, known liver (hepatic) carcinogens, and toxins (mycotoxins). Clinical and molecular medical analyses have yielded a considerable amount of information about liver carcinogenesis. Many genes undergo somatic aberrations, with a tendency to cluster at genes involved in cell cycle regulation, in the p53 and Wnt/catenin pathways of signal transduction and cellular adhesion, and in the TGF-beta/IGF axis. Since HCC may arise both in liver cirrhosis and in noncirrhotic liver, one may speculate that different hepatocarcinogenetic pathways exist. Recent results of high-output gene analysis using cDNA microarrays support the idea of different genetic alterations in HCC with or without cirrhosis.
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PMID:Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis. 1195 13

Primary hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, the viral-chemical etiology as well as molecular mechanisms of HCC pathogenesis remains largely unknown. Recent studies in our laboratory have identified several potential factors that may contribute to the pathogenesis of HCC. Oxidative stress and chronic inflammation have been linked to an increased risk of liver cancer. For example, oxyradical overload diseases such as Wilson disease and hemochromatosis result in the generation of oxygen/nitrogen species that can cause mutations in the p53 tumor suppressor gene. The Hepatitis B virus X gene (HBx), a viral transactivator with oncogenic potentials, has been shown to bind to and inactivate p53-mediated apoptosis. HBx mutants derived from HCC have a diminished ability to act as a transactivator. However, they still retain the ability to bind to and abrogate p53-mediated apoptosis. The comparison of gene expression profiles between HBx-expressing primary human hepatocytes and HBV-infected liver samples by cDNA microarrays indicate a unique alteration of a subset of oncogenes and tumor suppressor genes including p53. Our studies implicate both viral and endogenous chemical processes in the etiology of HCC, and p53 may be a common target for the inactivation during liver carcinogenesis.
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PMID:Molecular pathogenesis of human hepatocellular carcinoma. 1250 83

Primary hepatocellular carcinoma (HCC) is one of the most common malignancies and has the fourth highest mortality rate worldwide. The major risk factors, including chronic infections with the hepatitis B or C virus, are exposure to dietary aflatoxin B1(AFB1), vinyl chloride, or alcohol consumption. Southern China and sub-Saharan Africa have the highest dietary AFB1 exposure, making it and hepatitis B virus (HBV) the major causes of cancer mortality in these geographic areas. Recent studies have discovered genetic and epigenetic changes involved in the molecular pathogenesis of HCC, including somatic mutations in the p53 tumor suppressor gene (TP53). AFB1 induces typical G:C to T:A transversions at the third base in codon 249 of p53. Chronic active hepatitis B and C (HCV) infection, and further inflammatory and oxyradical disorders including Wilson disease (WD) or hemochromatosis, generate reactive oxygen/nitrogen species that can damage DNA and mutate the p53 gene. The X gene of HBV (HBx) is the most common open reading frame integrated into the host genome in HCC. The integrated HBx is frequently mutated and has a diminished ability to function as a transcriptional cotransactivator and to activate the NF-kappa B pathway. However, the mutant HBx proteins still retain their ability to bind to and abrogate p53-mediated apoptosis. In summary, both viruses and chemicals are implicated in the etiology and molecular pathogenesis of HCC. The resultant molecular changes in the ras and Wnt signal-transduction pathways, and the p53 and Rb tumor suppressor pathways significantly contribute to liver carcinogenesis
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PMID:TP53 and liver carcinogenesis. 1261 6

Hepatocellular carcinoma is one of the most prevalent tumors worldwide and its incidence is increasing due to hepatitis C virus infection. Other etiologic factors are hepatitis B virus infection, alcoholic liver disease and hemochromatosis. This tumor mainly develops in cirrhotic livers that are true precancerous states. Although mechanisms of hepatocarcinogenesis remain badly known, some signaling pathways are frequently deregulated: inactivation of the p53 tumor suppressor factor in 25% of HCC, activation of the Wnt signaling and the telomerase immortalization enzyme in most of tumors. Hepatitis viruses play a direct oncogenic role by interaction between viral proteins and cellular ones, which control cell homeostasis, or by integration of hepatitis B virus genome into the host genome. Furthermore, hepatitis viruses play an indirect oncogenic role by chronic inflammation and hepatocyte regeneration related to viral hepatopathy. In a near future, a better understanding of virus-specific oncogenic mechanisms should allow us to set up innovative preventive and curative therapeutic strategies.
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PMID:[Epidemiology, natural history and pathogenesis of hepatocellular carcinoma]. 1622 12

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the major risk factors include chronic infections with the hepatitis B (HBV) or C (HCV) virus, and exposure to dietary aflatoxin B(1) (AFB(1)) or alcohol consumption. Multiple genetic and epigenetic changes are involved in the molecular pathogenesis of HCC, for example, somatic mutations in the p53 tumor suppressor gene (TP53) and the activation of the WNT signal transduction pathway. AFB(1) frequently induces G:C to T:A transversions at the third base in codon 249 of TP53 and cooperates with HBV in causing p53 mutations in HCC. The detection of TP53 mutant DNA in plasma is a biomarker of both AFB(1) exposure and HCC risk. Chronic infection with HBV and HCV viruses, and oxyradical disorders including hemochromatosis, also generate reactive oxygen/nitrogen species that can both damage DNA and mutate cancer-related genes such as TP53. Certain mutant p53 proteins may exhibit a 'gain of oncogenic function'. The p53 biological network is a key responder to this oxidative and nitrosative stress. Depending on the extent of the DNA damage, p53 regulates the transcription of protective antioxidant genes and with extensive DNA damage, transactivates pro-oxidant genes that contribute to apoptosis. The X gene of HBV (HBx) is the most common open reading frame integrated into the host genome in HCC and the integrated HBx is frequently mutated. Mutant HBx proteins still retain their ability to bind to p53, and attenuate DNA repair and p53-mediated apoptosis. In summary, both viruses and chemicals are implicated in the etiology of TP53 mutations during the molecular pathogenesis of HCC.
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PMID:TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. 1740 25


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