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)

Cholangiocarcinoma (CCC) is relatively hypovascular, in contrast to hepatocellular carcinoma (HCC), which is often highly vascular. We investigated if the diminished vascularity of CCC is related to altered expression of thrombospondin-1 (TSP-1), an antiangiogenic factor, and/or vascular endothelial growth factor (VEGF), a potent angiogenic factor, comparing the relationships with those of high- and low-vascular HCC. We also investigated the relationship between the mutation of the p53 gene and TSP-1 expression or VEGF expression. Northern blot analysis and immunohistochemical staining were performed on surgically resected human CCC and HCC. The ratios of TSP-1 mRNA level in cancer cells versus adjacent noncancerous cells (T/N ratios) were significantly higher in CCC (n = 11) than in HCC with high vascularity (n = 15). In contrast, T/N ratios of VEGF mRNA level in CCC (n = 11) were comparable with those in HCC with low vascularity (n = 5). In CCC, the cancer cells and fibroblasts were positively stained with anti-TSP-1 antibody. We observed that T/N ratios of VEGF mRNA level, but not those of the TSP-1 mRNA level, were significantly correlated with vascularity in HCC. The relative increase in TSP-1 and the relative decrease in VEGF in tumors compared with normal tissue may underlie the limited angiogenesis of CCC. The p53 gene did not affect the expression of TSP-1 in CCC or VEGF in HCC.
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PMID:Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinoma. 982 14

Cholangiocarcinoma occurs frequently in patients with primary sclerosing cholangitis (PSC). We evaluated the incidence and prognostic significance of p53 protein overexpression and K-ras gene mutations in patients with biliary tract cancer and PSC. p53 protein expression was determined in specimens from 12 patients with biliary tract cancer, using the antibody, D07. K-ras mutations were detected using DNA sequencing and a mutation ligation assay. Accumulation of p53 protein was detected in 6 of 12 tumors (50%). K-ras mutations were detected in 4 of 12 tumors (33%). Overall survival in patients with p53-negative tumors was significantly longer (P < 0.05) than that in patients with p53-positive (mutant) tumors. Similarly, overall survival was significantly longer (P < 0.05) in the absence of a K-ras mutation than in patients with a tumor containing a K-ras mutation. Mean interval from the time of diagnosis of PSC until the diagnosis of biliary tract cancer was significantly shorter (P < 0.05) in patients with p53 overexpression than in those patients without p53 overexpression (2 versus 47 months). p53 overexpression and K-ras mutations occur commonly in patients with PSC and biliary tract cancer and are associated with a shortened survival. Patients with longstanding PSC are less likely to have these genetic alterations and may have a better prognosis.
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PMID:p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer. 1118 Aug 65

Cholangiocarcinoma (CCA) constitutes carcinoma of the bile duct found at a high prevalence in northeastern Thailand. In the present study, we examined the sera of altogether 82 Thai CCA patients for the presence of anti-p53 antibodies in order to investigate a role of the tumor suppressor gene, p53 in the carcinogenesis. Our results revealed anti-p53 antibodies in 7.3% of the cases tested, which conforms to the prevalence rate of p53 gene mutation recently reported at 5% among Thai patients. With limited number of the patients, anti-p53 antibodies were rapidly detected more frequently among patients with peripheral tumors than those with central tumors. However, further studies is required to establish significance and prognostic value of the antibodies in the context of CCA.
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PMID:Prevalence and clinical relevance of serum anti-p53 antibodies in patients with cholangiocarcinoma. 1127 Apr 75

Cholangiocarcinomas are malignant tumors of the intra- or extrahepatic biliary tract. An increasing incidence of cholangiocarcinomas has been documented. This increase might be only apparent, due to the progress in investigation and changes in tumor codification. The major clinical sign of cholangiocarcinomas is obstructive jaundice, which is persistent and progressive. Biological tumor markers are nonspecific: an increased serum level of carcinoembryonic antigen is relevant when associated with an increased level of CA 19-9 or CA-125. K-ras mutation and aberrant expression of p53 are present in one third of intrahepatic cholangiocarcinomas. The firstline imaging investigation is ultrasonography, which always detects dilatation of the bile ducts, but more rarely the tumor itself. Classically, endoscopic retrograde cholangiopancreatography (ERCP), the "gold standard" investigation in case of obstructive jaundice, has been performed following ultrasonography. The actual recommendations, based on grade B and C evidences, are to start investigations with ultrasonography and to continue with noninvasive methods: MRI/MRCP or spiral CT, whenever a malignant obstructive jaundice is suspected. Invasive cholangiography (ERCP, PTC) should be reserved for tissue diagnosis or therapeutic decompression when cholangitis is present, or for stent insertion in unresectable tumors. If MRI, CT or cholangiography do not exclude resectability, hepatic arteriography and portal vein evaluation should be performed preoperatively. All patients who do not have unequivocal cholangiographic and angiographic signs of unresectability should undergo surgery, in order to benefit of a possible tumor resection. The radical surgical procedures relieve the obstruction and jaundice by resecting the tumor. The palliative (surgical or endoscopic) procedures cure the jaundice, but do not remove the tumor. Prognosis of cholangiocarcinomas is dismal, although five-year survival rates for these tumors have improved due progress in surgery and adjuvant oncological therapy.
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PMID:Cholangiocarcinoma: risk factors, diagnosis and management. 1552 94

Cholangiocarcinomas are intrahepatic bile duct carcinomas that are known to have a poor prognosis. Sesquiterpene lactone parthenolide, which is the principal active component in medicinal plants, has been used to treat tumors. Parthenolide effectively induced apoptosis in all four cholangiocarcinoma cell lines in a dose-dependent manner. However, the sarcomatous SCK cells were more sensitive to parthenolide than the other adenomatous cholangiocarcinoma cells. Therefore, this study investigated whether or not the expression of p53, the Fas/Fas ligand (FasL), Bcl-2/Bcl-X(L) determines the enhanced drug susceptibility of SCK cells. The results showed that Bcl-2 family molecules, such as Bid, Bak, and Bax, are involved in the parthenolide-induced apoptosis and that the defective expression of Bcl-X(L) might contribute to the higher parthenolide sensitivity in the SCK cells than in the other adenomatous cholangiocarcinoma cells. SCK cells, which stably express Bcl-X(L), were resistant to parthenolide, whereas Bcl-X(L)-positive Choi-CK cells transfected with the antisense Bcl-X(L) showed a higher parthenolide sensitivity than the vector control cells. Molecular dissection revealed that Bcl-X(L) inhibited the translocation of Bax to the mitochondria, decreased the generation of intracellular reactive oxygen species, reduced the mitochondrial transmembrane potential (deltapsi(m)), decreased the release of cytochrome c, decreased the cleavage of poly(ADP-ribose) polymerase, and eventually inhibited apoptotic cell death. These results suggest that parthenolide effectively induces oxidative stress-mediated apoptosis, and that the susceptibility to parthenolide in cholangiocarcinoma cells might be modulated by Bcl-X(L) expression in association with Bax translocation to the mitochondria.
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PMID:Susceptibility of cholangiocarcinoma cells to parthenolide-induced apoptosis. 1602 33

Cholangiocarcinoma development may be related to cholangiocyte DNA damage from genotoxic compounds in bile. We have previously shown that human biliary tissue is exposed to genotoxic agents, as evidenced by the presence of DNA adducts. Establishing the presence of a 'mutational signature' in tumour suppressor genes from tumour tissue provides a means of linking cause and effect in human cancer. Inactivation of p53, known to have 'hot-spots' for particular chemical carcinogens, has previously been linked to human cholangiocarcinoma. However, previous p53 studies have focused on exons 5-8, potentially missing gene alterations at other sites. This study examined the putative link between environmental carcinogens and intrahepatic cholangiocarcinoma by analysing DNA from 31 patients for complete p53 mutational signatures, using single strand conformational polymorphism and polymerase chain reaction. All mutations found were compared to known p53 mutations in cholangiocarcinoma and to mutations induced by environmental mutagens, as described in p53 databases. Five non-silent p53 mutations were found, including three new frameshift mutations and two new intron mutations which have not previously been reported in cholangiocarcinoma. Two frameshifts were due to deletions and the third due to an insertion in exon 5. There was no predominant mutational spectrum amongst the set of cholangiocarcinoma samples studied, or on combining these mutations with the dataset of known p53 mutations in cholangiocarcinoma. Several reasons may explain this, including lack of data outside exons 5-8, bias in mutation reporting, the involvement of mutations in non-coding regions or genes other than p53, or the possibility that there is no carcinogenic specific agent and therefore no signature.
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PMID:Analysis of p53 mutations for a mutational signature in human intrahepatic cholangiocarcinoma. 1659 44

Cholangiocarcinoma of intrahepatic and extrahepatic bile ducts has a multistep carcinogenesis. Two premalignant lesions have been suggested for invasive cholangiocarcinoma: biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. How the carcinogenetic process differs between biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct is not clear. In this study, we performed a pathological study to reveal the expression of key molecules related to the cell cycle during 2 carcinogenetic lineages. We immunohistochemically examined the expression of p21, p53, cyclin D1, and Dpc4 in a total of 89 cases: nonneoplastic biliary epithelium, biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, and invasive cholangiocarcinoma. The expression of p21, p53, and cyclin D1 was up-regulated with histological progression in both biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct, whereas Dpc4 expression was down-regulated in these 2 lineages. In biliary intraepithelial neoplasia, p21 expression was significantly up-regulated early on. In contrast, levels of all molecules changed gradually in intraductal papillary neoplasm of the bile duct. Changes in p53 expression during histological progression differed significantly between biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. p53 expression was dramatically up-regulated at the invasive stage of biliary intraepithelial neoplasia, whereas it was quite low in noninvasive biliary intraepithelial neoplasia. In contrast, p53 expression was already up-regulated in low-grade intraductal papillary neoplasm and reached a plateau in high-grade intraductal papillary neoplasm and invasive cholangiocarcinoma. This study suggested p21, p53, cyclin D1, and Dpc4 to be involved in the carcinogenesis of both biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. p53 expression was regulated differently in biliary intraepithelial neoplasia compared with intraductal papillary neoplasm of the bile duct.
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PMID:Expression of cell cycle-related molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm. 1849 10

Cholangiocarcinoma is the second most common malignant tumor of the liver. We analyzed, immunohistochemically, the significance of cell cycle- and apoptosis-related markers in 128 cholangiocarcinomas (42 intrahepatic, 70 extrahepatic, and 16 gallbladder carcinomas) combined in a tissue microarray. Follow-up was available for 57 patients (44.5%). In comparison with normal tissue (29 specimens), cholangiocarcinomas expressed significantly more frequently p53, bcl-2, bax, and COX-2 (P.05 <). Intrahepatic tumors were significantly more frequently bcl-2+ and p16+, whereas extrahepatic tumors were more often p53+ (P < .05). Loss of p16 expression was associated with reduced survival of patients. Our data show that p53, bcl-2, bax, and COX-2 have an important role in the pathogenesis of cholangiocarcinomas. The differential expression of p16, bcl-2, and p53 between intrahepatic and extrahepatic tumors demonstrates that there are location-related differences in the phenotype and the genetic profiles of these tumors. Moreover, p16 was identified as an important prognostic marker in cholangiocarcinomas.
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PMID:Clinical significance of cell cycle- and apoptosis-related markers in biliary tract cancer: a tissue microarray-based approach revealing a distinctive immunophenotype for intrahepatic and extrahepatic cholangiocarcinomas. 1885 71

Cholangiocarcinoma (CC) is an intrahepatic bile duct carcinoma with a high mortality rate and a poor prognosis. Sarcomatous change/epithelial mesenchymal transition (EMT) of CC frequently leads to aggressive intrahepatic spread and metastasis. The aim of this study was to identify the genetic alterations and gene expression pattern that might be associated with the sarcomatous change in CC. Previously, we established 4 human CC cell lines (SCK, JCK1, Cho-CK, and Choi-CK). In the present study, we characterized a typical sarcomatoid phenotype of SCK, and classified the other cell lines according to tumor cell differentiation (a poorly differentiated JCK, a moderately differentiated Cho-CK, and a well differentiated Choi-CK cells), both morphologically and immunocytologically. We further analyzed the genetic alterations of two tumor suppressor genes (p53 and FHIT) and the expression of Fas/FasL gene, well known CC-related receptor and its ligand, in these four CC cell lines. The deletion mutation of p53 was found in the sarcomatoid SCK cells. These cells expressed much less Fas/FasL mRNAs than did the other ordinary CC cells. We further characterize the gene expression pattern that is involved in the sarcomatous progression of CC, using cDNA microarrays that contained 18,688 genes. Comparison of the expression patterns between the sarcomatoid SCK cells and the differentiated Choi-CK cells enabled us to identify 260 genes and 247 genes that were significantly over-expressed and under-expressed, respectively. Northern blotting of the 14 randomly selected genes verified the microarray data, including the differential expressions of the LGALS1, TGFBI, CES1, LDHB, UCHL1, ASPH, VDAC1, VIL2, CCND2, S100P, CALB1, MAL2, GPX1, and ANXA8 mRNAs. Immunohistochemistry also revealed in part the differential expressions of these gene proteins. These results suggest that those genetic and gene expression alterations may be relevant to the sarcomatous change/EMT in CC cells.
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PMID:Genetic and expression alterations in association with the sarcomatous change of cholangiocarcinoma cells. 1928 91

Cholangiocarcinoma is the second most common primary hepatic neoplasia and the only curative therapy is surgical resection or liver transplantation. Biphosphonates (BPs) are an emerging class of drugs widely used to treat bone diseases and also appear to possess direct antitumor activity. In two human cholangiocarcinoma cell lines (TFK-1 and EGI-1) we investigated, for the first time, the activity of zoledronic acid by determining proliferation, cell cycle analysis and apoptosis. The results obtained indicate that zoledronic acid induces cell-narrowing and growth inhibition, both reversed by 25 microM GGOH, and significantly affects the colony-forming ability of these cells. The inhibition by zoledronic acid of Rap1A prenylation was reversed in cell co-treated with GGOH. At 10-50 microM zoledronic acid exerted an S-phase cell cycle arrest which was confirmed by changes in the level of cyclins and of regulators p27(KIP1) and pRb. Interestingly, the expression level of cyclin A (putative S-phase marker) shows a dose-dependent increment in contrast to the decrement of cyclin D1 (putative G1 phase marker). However, neither hypodiploid cells nor cleaved PARP or caspase-3 was detected. The lack of TP53 or loss of its function, the large constitutive expressions of anti-apoptotic proteins Bcl-xL and HSP27 together with the low level of the pro-apoptotic Bax are the likely factors which protect cells from apoptosis. In conclusion, our study indicates that zoledronic acid induces S-phase arrest and cell-narrowing, both reversed by GGOH and, by changing the delicate balance between pro- and anti-apoptotic proteins, allows survival of cholangiocarcinoma cells.
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PMID:Zoledronic acid determines S-phase arrest but fails to induce apoptosis in cholangiocarcinoma cells. 1946 30


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