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)

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

Aberrations of the p53 gene were observed in high frequency in HCCs in China, Mozambique and Japan. Most of the mutations were G to T transversions in codon 249 of the p53 gene in HCCs in China and Mozambique, where aflatoxin B1 was a risk factor. These findings strongly suggest that aflatoxin B1 induced this type of mutations. On the other hand, in Japanese HCCs, no mutation was observed in codon 249, indicating a different cause of HCC development. Pathological analyses revealed that p53 mutations were detected only in advanced HCCs and not in early HCCs. In addition, aberrations of the RB gene were observed in only tumors carrying mutated p53 gene. These results indicate the involvement of at least two tumor suppressor genes in a late stage of hepatocarcinogenesis. Possible mechanisms of HCC formation are discussed.
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PMID:[Co-inactivation of the p53 and RB genes in human hepato cellular carcinoma]. 809 51

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

Hepatocellular carcinoma samples obtained from 59 patients at surgical resection were examined for mutations of the third base at codon 249 of the p53 gene, using the polymerase chain reaction and oligonucleotide hybridization techniques. This point mutation, which is frequently observed in HCC cases from Southern Africa and Quidong in China, was not recognized in either 60 hepatocellular carcinomas or 53 noncancerous liver tissue samples from Japan. Thirty-four of 45 patients (75.6%) were positive for the hepatitis C virus, which was a higher rate than that for hepatitis B virus infection (9 of 55; 16.4%). The exposure to aflatoxin B1 was not considered to be remarkable. These results suggest that the point mutation of the third base at codon 249 is not common in Japanese patients, and it is suggested that numerous other factors affect the mutation of the p53 gene and the development of hepatocellular carcinoma.
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PMID:The mutation of codon 249 in the p53 gene is not specific in Japanese hepatocellular carcinoma. 825 41

The tumor suppressor p53 exerts important protective functions towards DNA-damaging agents. Its inactivation by allelic deletions or point mutations within the P53 gene as well as complex formation of wildtype p53 with cellular or viral proteins is a common and crucial event in carcinogenesis. Mutations increase the half-life of the p53 protein allowing the immunohistochemical detection and anti-p53 antibody formation. Distinct G to T point mutations in codon 249 leading to a substitution of the basic amino acid arginine by the neutral amino acid serine are responsible for the altered functionality of the mutant gene product and were originally identified in 8 of 16 Chinese and 5 of 10 African HCC patients. Both groups are frequently exposed to mycotoxin contaminations of their food. Today an average P53 gene mutation rate of 25% is assumed for high-aflatoxin B1-exposure regions. This is double the rate observed in low-aflatoxin B1-exposure countries. Although many HCC patients displaying P53 mutations also suffer from HBV infection, which itself can lead to rearrangements of P53 coding regions or induce the synthesis of viral proteins possibly interacting with p53, the specific G to T transversion within codon 249 of the P53 gene seems to directly reflect the extent of aflatoxin B1 exposure.
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PMID:Point mutations of the P53 gene, human hepatocellular carcinoma and aflatoxins. 830 Oct 66

The molecular role of hepatitis C virus (HCV) in liver disease has yet to be clarified. In this study, we analyzed the relationship of HCV replication with mRNA expression of growth factors and mutation of tumor suppressor gene, ie, transforming growth factor-beta 1 (TGF-beta 1), which promotes cirrhotic changes; TGF-alpha, insulin-like growth factor-II (IGF-II), which are both related to hepatocyte transformation; and tumor suppressor gene p53, which is associated with HCC progression. A semiquantitative RNA polymerase chain reaction (RNA-PCR) was used to analyze genetic expression in 31 cirrhotic liver specimens from patients with HCV. In order to detect HCV replication, the minus-strand RNA of HCV, which serves as a template for the synthesis of genomic plus-strand RNA, was examined. The expression of the growth factors was semiquantified by RNA-PCR, and the mutation of p53 was detected using PCR-single-strand conformation polymorphism. According to the semiquantitative analysis, HCV replication was not associated with the expression of TGF-beta 1 but was significantly so with the overexpression of TGF-alpha (r = 0.74) and IGF-II (r = 0.65) in the HCV-positive cirrhotic livers. No mutation of p53 was recognized in any of the samples. Our investigation thus suggested that the replication of HCV might mediate the coexpression of TGF-alpha and IGF-II and act as a possible initiating factor for hepatocarcinogenesis.
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PMID:Hepatitis C virus replication is associated with expression of transforming growth factor-alpha and insulin-like growth factor-II in cirrhotic livers. 856 58

A series of 60 cases of oxyphilic (Hurthle cell) carcinomas (HCC) of the thyroid were reviewed to determine whether it is possible to correlate morphologic and clinical features as a means of assessing prognosis. Twenty cases showing predominant solid or trabecular patterns (as described in poorly differentiated carcinomas with a follicular pattern) were selected and the clinicopathological features were investigated. Based on cell size, two groups of solid or trabecular HCCs were identified: The first group (17 cases) was made up of typical large granular oxyphilic cells, and the second (three cases) had small oxyphilic cells. All tumors were reactive for thyroglobulin and for a mitochondrial antigen, selectively marking oxyphilic, mitochondrial-rich cells. Nuclear pleomorphism in individual cells was a common feature, but foci of anaplastic carcinoma were never found. Four cases overexpressed p53 protein and 10 expressed bcl-2 gene product. At follow-up, among the high-stage (pT3-pT4) tumors, seven patients had recurrences or metastases, six of whom were alive with disease or died of disease. In the control group of HCC with predominant follicular patterns, only one of 40 cases had a fatal outcome. The difference was statistically significant. Small-cell patterns and a p53 protein-positive/bcl-2 gene product negative phenotype were features of clinically aggressive HCC cases. We suggest that within the spectrum of oxyphilic (Hurthle cell) tumors, poorly differentiated HCC showing solid or trabecular patterns are a distinct group, based on both morphological and clinical features.
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PMID:Poorly differentiated oxyphilic (Hurthle cell) carcinomas of the thyroid. 865 47

Immunohistochemistry (ABC method) and in situ hybridization (DNA-RNA) were used to detect c-myc and p53 gene expression in tissues of human HCC and nearby non-tumorous liver (NT) from 23 patients. The results showed that the positive rates of P62c-myc were 87% (20/23) in HCC and 91% (21/23) in NT. The positive rates of P53 protein were 39% (9/23) in HCC as well as in NT. The positive rates of c-myc and p53 mRNA were 70% (16/23) and 56% (13/23) in HCC and NT respectively. The expression of c-myc and p53 at protein level was significantly correlated with that at mRNA level. These observations suggest a close association of c-myc and p53 gene overexpression with hepatocarcinogenesis. Immunohistochemistry (ABC method) on section of paraffin embedded tissue is a reliable method for detecting c-myc and p53 gene expression in HCC.
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PMID:[Overexpression of c-myc and p53 gene in human hepato-cellular carcinoma--a study with immunohistochemistry and in situ hybridization]. 869 90

Some of the multiple factors involved in the molecular pathogenesis of hepatocellular carcinoma have been elucidated in recent years but no clear picture of how and in what sequence these factors interact at the molecular level has emerged yet. Transformation of hepatocytes to the malignant phenotype may occur irrespective of the aetiological agent through a pathway of chronic liver injury, regeneration and cirrhosis. The activation of cellular oncogenes, the inactivation of tumour suppressor genes and overexpression of certain growth factors contribute to the development of HCC. There is increasing evidence that the hepatitis B virus may play a direct role in the molecular pathogenesis of HCC. Aflatoxins have been shown to induce specific mutations of the p53 tumour suppressor gene thus providing a clue to how an environmental factor may contribute to tumour development at the molecular level.
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PMID:The molecular pathogenesis of hepatocellular carcinoma. 879 May 56

Cancer is thought to arise from the accumulation of several genetic mutations in a single cell. These include integration of viral genomes, activation of protooncogenes and inactivation of tumor suppressor genes. HCC is one of the most common cancers in Asia and Africa. Various studies have revealed its association with hepatitis B or C viral infection. While activation of known protooncogenes, such as ras genes does not seem to play an important role, frequent allelic loss on specific chromosomal arms, 4q, 13q, 16q and 17p, indicates that dysfunction of diverse tumor suppressor genes located on these chromosome arms is involved in the development of HCC. An informative p53 mutational spectrum of frequent G to T transversions in codon 249 is found in HCCs from either Qidong, People's Republic of China, or southern Africa. This observation links exposure to aflatoxin B1, a known cancer risk factor in these geographic regions. Recently, we found that expression of syndecan-1, which is a transmembrane heparan sulfate proteoglycan involved in cell matrix interactions and growth factor bindings, was inversely associated with metastatic potential in human hepatocellular carcinoma as like nm23-H1 expression was. Transfection with syndecan-1 gene suppresses invasive activity of hepatoma cells. These data support our hypothesis that syndecan-1 is one of important metastasis suppressor factors in hepatoma cells. PR-39 is a proline-rich antimicrobial peptide which was isolated from a pig small intestine and has been reported to induced syndecan-1 on mouse mesenchymal cells. Transfection with PR-39 gene caused induction of syndecan-1 and altered invasive phenotype and actin structure on hepatoma cells. Syndecan-1 and PR-39 may serve as a basis for design of drug or gene therapy effective against metastasis of hepatocellular carcinomas.
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PMID:[Alteration of genomic structure and/or expression of cancer associated genes in hepatocellular carcinoma]. 949 32


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