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)

Synchronous multiple primary malignancies are relatively unusual. We describe a case of synchronous triple cancers located at the middle and lower esophagus and the stomach in a 59-year-old Taiwanese man who presented with progressive dysphagia, epigastralgia, and bodyweight loss in 1 month. Endoscopic and histological features, microsatellite instability status of genomic DNA, and immunohistochemical staining of p53, MUC2, Fhit, c-erbB-2 and E-cadherin of all three cancers were demonstrated. We noted that these three cancers arose from different clones and that p53 mutation, instead of microsatellite instability, may play a major role in the development of multiple primary malignancies in this patient.
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PMID:Synchronous triple cancers at middle and lower esophagus and stomach with different histological features and genetic alterations. 1210 Jun 22

MUC2 is one of the major components of mucins that provide a protective barrier between epithelial surfaces and the gut lumen. We investigated possible alterations of MUC2 gene expression by p53 and p21(Sdi1/Waf1/Cip1) in a human colon cancer cell line, DLD-1, establishing subclones in which a tetracycline-regulatable promoter controls exogenous p53 and p21 expression. MUC2 mRNA more significantly increased in response to p53 than to p21. Unexpectedly, MUC2 expression was also induced in human osteosarcoma cells, U-2OS and Saos-2, by exogenous p53. We next performed a reporter assay to test the direct regulation of MUC2 gene expression by p53. Deletion and mutagenesis of the MUC2 promoter region showed that it contains two sites for transactivation by p53. Furthermore, an electrophoretic mobility shift assay indicated that p53 binds to those elements. We analyzed MUC2 expression in other cell types possessing a functional p53 after exposure to various forms of stress. In MCF7 breast cancer and A427 lung cancer cells, MUC2 expression was increased along with the endogenous p53 level by actinomycin D, UVC, and x-ray, but not in RERF-LC-MS lung cancer cells carrying a mutated p53. These results suggest that p53 directly activates the MUC2 gene in many cell types.
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PMID:Transcriptional activation of the MUC2 gene by p53. 1237 98

The aim of this study was to clarify the mechanism of malignant transformation of gastric hyperplastic polyps, focusing on phenotypic expression, cell proliferation, and p53 overexpression. Twenty-two lesions of gastric hyperplastic polyps with neoplastic foci were selected for this study. The phenotypes were divided into 3 types (G, gastric; incomp I, incomplete intestinal; and comp I, complete intestinal), according to immunohistochemical stains (human gastric mucin [HGM], MUC2, and CD10). The cell proliferative activity by Ki-67 and overexpression of p53 protein were also examined. Eleven of these lesions contained carcinoma components (CA, category 5 by the Vienna classification), 6 of which were accompanied by low-grade dysplasia (LGD, category 3) and 4 of which were accompanied by high-grade dysplasia (HGD, category 4). Another 2 were composed only of HGD, and the remaining 9 were composed of both LGD and HGD components. As a result, 15 LGD, 15 HGD, and 11 CA components were recognized. The 15 LGD components were classified as 1 G type and 14 incomp I type. All hyperplastic components expressed HGM, 5 (22.7%) of which were accompanied by focal intestinal metaplasia demonstrated by MUC2 expression, whereas intestinalization frequently occurred in neoplastic components (93% of LGD, 53% of HGD, and 64% of CA components). The labeling index was 22.2% in hyperplastic, 42.2% in LGD, 55.7% in HGD, and 53.9% in CA components. p53 protein overexpression was recognized in none of hyperplastic, in 40% of the LGD, in 60% of the HGD, and in 45% of the CA components. These results suggest the importance of the dysplasia-carcinoma sequence in malignant transformation of hyperplastic polyps. Interestingly, intestinalization frequently occurs during neoplastic transformation, although it is not common in the surrounding hyperplastic components.
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PMID:Malignant transformation of gastric hyperplastic polyps: alteration of phenotypes, proliferative activity, and p53 expression. 1239 75

To clarify the biological impact and molecular pathogenesis of cellular phenotype in differentiated-type gastric cancers (DGCs), we investigated cell kinetics and genetic instabilities in early stage of DGCs. A total of 43 early gastric cancers (EGCs) were studied. EGCs were divided into 3 phenotypic categories: gastric (G type, n = 11), ordinary (O type, n = 20), and complete intestinal (CI type, n = 12) based on the combination of HGM, ConA, MUC2, and CD10. Proliferative index (PI), apoptotic index (AI), and p53 overexpression were investigated by immunohistochemical staining with anti-Ki-67, the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method, and p53 antibody, respectively. Using a high-resolution fluorescent microsatellite analysis system, microsatellite instability (MSI) and loss of heterozygosity (LOH) were examined. Frameshift mutation analysis of transforming growth factor-beta type II receptor (TGF-betaRII) and bcl-2-associated X (BAX) in cancers with MSI was also performed. The mean AI/PI ratio values were 0.04 for G-type, 0.10 for O-type, and 0.13 for CI-type cancers--significantly lower in G type than in O and CI types (P = 0.02 and P = 0.001, respectively). No difference in the incidence of MSI and LOH was seen among the 3 cellular phenotypes. However, the major pattern of MSI, which showed drastic and widely dispersed changes and is related to an increased risk for cancer, was significantly higher in G and O types than in CI type (P <0.005). No frame shift mutations of TGF-betaRII or BAX were found in CI-type cancers. These results indicate that G-type cancers are likely to show more aggressive behaviors than CI-type cancers, and that O-type cancers show the intermediate characteristics of both types. However, the molecular pathogenesis of each phenotypic cancer is not associated with microsatellite alterations.
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PMID:Cell kinetics and genetic instabilities in differentiated type early gastric cancers with different mucin phenotype. 1260 64

Our report describes a 66-yr-old man who underwent surgical resection of the pancreas twice within a period of 3 yr for primary and recurrent intraductal papillary mucinous tumors (IPMTs). During the second operation, a minute invasive ductal carcinoma (IDC) was accidentally discovered in the resected specimen of the residual pancreas. The similarity and continuity between this IDC and recurrent IPMT were not recognized histologically. A solid tumor was found in the hepatoduodenal ligament 3 mo after the second operation. We performed a third operation, performing laparotomy and intra-operative radiotherapy, but could not extirpate the tumor. A biopsy specimen obtained from the tumor during this third operation revealed adenocarcinoma, and the patient later died because of tumor progression. We immunohistochemically analyzed the expression of HER-2/neu, Smad4, p16, p21, p53, mucin immunophenotypes and the Ki-67 labeling index in this series of pancreatic-duct neoplasias. Overexpression of HER-2/neu and loss of Smad4 were detected in the minute IDC, which was very different from the immunohistochemical features of both the primary and recurrent IPMTs. The IDC also showed a MUC1-positive/MUC2-negative phenotype. Therefore, we suggest that de novo IDC may occur in IPMT patients, especially those with multiple tumor recurrence. The present case may be helpful in understanding the pathogenesis of pancreatic duct lesions.
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PMID:Minute invasive ductal carcinoma of the residual pancreas after distal pancreatectomy for intraductal papillary-mucinous tumor. 1262 31

There are a large number of stable pancreatic ductal carcinoma cell lines that are used by researchers worldwide. Detailed data about their differentiation status and growth features are, however, often lacking. We therefore attempted to classify commonly used pancreatic carcinoma cell lines according to defined cell biological criteria. Twelve pancreatic ductal adenocarcinoma cell lines were cultured as monolayers and spheroids and graded according to their ultrastructural features. The grading system was based on the integrity of membrane structures and on the presence of mucin granules, cell organelles, nuclear and cellular polymorphism, cell polarity, and lumen formation. On the basis of the resulting scores the cell lines were classified as well, moderately, or poorly differentiated. In addition, immunocytochemistry was performed for the markers cytokeratin 7, 8, 18, 19, carcinoembryonic antigen, MUC1 MUC2, MUC5, and MUC6. The population doubling time of monolayer cultures, determined by a tetrazolium salt based proliferation assay was correlated with the ultrastructural grade. The grading of the ultrastructural features of the monolayers, and particularly of the spheroids, revealed that Capan-1 and Capan-2 cells were well differentiated; Colo357, HPAF-2, Aspc-1, A818-4, BxPc3, and Panc89 cells were moderately differentiated and PancTu-I, Panc1, Pt45P1, and MiaPaCa-2 cells poorly differentiated. Membrane-bound MUC1 staining was a characteristic of well differentiated cell lines. The population doubling time of the monolayer cultures was related to the differentiation grade. No relationship was found between the p53, K-ras, DPC4/Smad4, or p16(INK4a) mutation status and the grade of differentiation. We conclude that the proposed ultrastructural grading system combined with the proliferative activity provides a basis for further comparative studies of pancreatic ductal adenocarcinoma cell lines.
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PMID:A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform. 1269 24

The loss of tumour suppressor genes (TSGs) is a key event in many human cancers, including gastric carcinoma. Many TSG candidates have been studied, but their roles in gastric carcinogenesis remain unclear. To clarify the clinical significance of TSG expression in gastric carcinoma, the expression of various TSG candidates (p53, E-cadherin, FHIT, smad4, rb, VHL, PTEN, MGMT, p16, and KAI1), as well as other proteins (bcl-2, MUC1, MUC2, MUC5AC, MUC6, CEA, CD44, beta-catenin, C-erbB2, and cyclin B2), was evaluated immunohistochemically in 329 consecutive gastric carcinomas using the tissue array method. The overexpression of p53 and MUC1 (p < 0.01) and the loss of expression of smad4 (p = 0.04), FHIT (p = 0.03), MGMT (p = 0.01), E-cadherin, KAI1, and PTEN (p < 0.01) were found to be significantly associated with poor gastric carcinoma prognosis. Seven out of eight survival-associated proteins were found to be protein products of TSGs. The gastric carcinomas were divided into five groups according to the grade of alteration in TSG expression. No TSG expression loss was found in 32 cases (TSG1). One TSG loss was found in 47 cases (TSG2), two in 67 cases (TSG3), three or four in 64 cases (TSG4), and five, six, or seven in 38 cases (TSG5). The grade of TSG expression was confirmed to be significantly associated with WHO classification (p = 0.04), pTNM stage, lymphatic invasion, and patient survival (p < 0.01 for the latter three). By multivariate analysis, the grade of TSG expression was found to be significantly and independently associated with patient survival (p < 0.01). In conclusion, the findings of this study suggest that the cumulative loss of TSG expression in gastric carcinoma is important in determining patient survival.
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PMID:Tumour suppressor gene expression correlates with gastric cancer prognosis. 1269 39

A multistep model for pancreatic adenocarcinoma has been proposed recently. In this model, well-defined, noninvasive ductal lesions are recognized as precursors of invasive cancer and have been classified under the nomenclature of pancreatic intraepithelial neoplasia, or PanIN. Increasing evidence suggests that PanINs represent true neoplasms of the pancreatic ductal epithelium, accumulating histologic and genetic abnormalities in their progression toward invasive cancer. We have constructed a tissue microarray containing 55 PanIN lesions of all histologic grades in order to perform a multicomponent analysis of the pancreatic adenocarcinoma progression model. The protein products of 14 genes encompassing a variety of functional classes, such as tumor suppressor genes (p53, Smad4/Dpc4), oncogenes (beta-catenin), cell cycle antigens (p16, cyclin D1), proliferation antigens (Ki-67, topoisomerase II alpha), and epithelial apomucins (MUC1, MUC2, MUC5), as well as "novel" genes described as differentially up-regulated in invasive pancreas cancer by global microarray expression analysis (mesothelin, prostate stem cell antigen, fascin, and 14-3-3varsigma), were analyzed by immunohistochemistry on the PanIN tissue microarray. Comparison of the results from the current study with previously published data performed on routine histologic sections of PanINs demonstrates that tissue microarrays are a valid platform for molecular analysis not only of invasive cancers but of precursor lesions as well. In addition, this study demonstrates that molecular abnormalities in PanINs are not random but can usually be stratified into "early" changes (e.g., expression of MUC5 and prostate stem antigen, or loss of p16), "intermediate" changes (e.g., expression of cyclin D1), and "late" changes (e.g., expression of p53, proliferation antigens, MUC1, mesothelin, and 14-3-3varsigma, or loss of Smad4/Dpc4). Understanding the molecular pathogenesis of precursor lesions of invasive pancreatic adenocarcinomas using a high-throughput tissue microarray-based approach is a valuable adjunct to designing rational strategies for early detection of this lethal neoplasm.
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PMID:Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. 1367 54

A case of mucinous cystadenoma of the testis in a 55-year-old man is reported. The tumor was confined to the testis and was clearly separated from the epididymis. There was no connection between the tumor cyst and the rete testis. The lumen of the cyst was lined with a single-layer of columnar cells interspersed with goblet cells. There was neither stromal invasion nor metastasis to other organs and there were no ovarian or germ cell neoplastic elements in the tumor. Immunohistochemical analysis revealed that MUC2, MUC5AC, carcinoembryonic antigen, CA19-9, CK7 and CK20 proteins were expressed on the tumor epithelial cells, whereas expression of MUC6, alpha-fetoprotein, CA125, human chorionic gonadotrophin, estrogen receptor, progesterone receptor, calretinin, chromogranin A, p53, cyclin D1 and bcl-2 proteins was absent. Ki-67 protein was weakly and sparsely expressed in the nuclei of epithelial cells. The mucinous cystadenoma in the present case, which was devoid of a connection to testicular appendices and had the immunohistochemical characteristics of gastrointestinal mucosa, might have originated from one-sided differentiation of teratoma cells.
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PMID:Immunohistochemical examination of mucinous cystadenoma of the testis. 1508 41

There are differing views between Western and Japanese pathologists on the use of histological criteria to classify gastrointestinal tumors. It is therefore a priority to create a new histological classification of the stomach in order to resolve the confusion. Expression patterns were examined of mucin (MUC2, CD10, MUC5AC, pyloric gland-type mucin), p53 protein, and Ki-67 in tumor cells according to the following new classification system for differentiated-type intramucosal neoplastic lesions of the stomach, based on nuclear atypia: borderline neoplasia (adenoma (including dysplasia), indefinite tumor of adenoma or low-grade cancer, and low-grade cancer) and definite carcinoma (intermediate cancer, and high-grade cancer). The resulting grades were: adenoma, 23; indefinite tumor for adenoma or low-grade cancer, 6; low-grade cancer, 28; intermediate cancer, 48; high-grade cancer, 20. While the frequency of intestinal-type borderline neoplasias was higher than that of definite carcinomas, the mixed-type of definite carcinomas occurred with higher frequency than borderline neoplasias. The p53 protein overexpression and the Ki-67-positive rate increased with an increase in the grade assigned according to the new classification. The correlated expression levels of p53 protein, Ki-67, and various mucins, support the conclusion that this classification of intramucosal neoplastic lesions is useful for obtaining a consensus diagnosis of gastric intramucosal neoplasia between pathologists and gastrointestinal clinicians.
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PMID:Analysis of mucin, p53 protein and Ki-67 expressions in gastric differentiated-type intramucosal neoplastic lesions obtained from endoscopic mucosal resection samples: a proposal for a new classification of intramucosal neoplastic lesions based on nuclear atypia. 1514 2


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