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)

Most head and neck squamous cell carcinoma (HNSCC) patients present with late-stage cancers, which are difficult to treat. Therefore, early diagnosis of high-risk premalignant lesions and incipient cancers is important. HNSCC is currently perceived as a single progression mechanism, resulting in immortal invasive cancers. However, we have found that approximately 40% of primary oral SCCs are mortal in culture, and these have a better prognosis. About 60% of oral premalignancies (dysplasias) are also mortal. The mortal and immortal tumors are generated in vivo as judged by p53 mutations and loss of p16(INK4A) expression being found only in the original tumors from which the immortal cultures were derived. To investigate the relationships of dysplasias to SCCs, we did microarray analysis of primary cultures of 4 normal oral mucosa biopsies, 19 dysplasias, and 16 SCCs. Spectral clustering using the singular value decomposition and other bioinformatic techniques showed that development of mortal and immortal SCCs involves distinct transcriptional changes. Both SCC classes share most of the transcriptional changes found in their respective dysplasias but have additional changes. Moreover, high-risk dysplasias that subsequently progress to SCCs more closely resemble SCCs than nonprogressing dysplasias. This indicates for the first time that there are divergent mortal and immortal pathways for oral SCC development via intermediate dysplasias. We believe that this new information may lead to new ways of classifying HNSCC in relation to prognosis.
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PMID:Divergent routes to oral cancer. 1688 35

Sulindac sulfide and sulindac sulfone have demonstrated anti-neoplastic and chemo-preventive activity against various human tumors, but few studies have examined the relative effectiveness of these drugs against squamous cell carcinoma of the head and neck (SCCHN). These compounds are metabolites of the nonsteroidal anti-inflammatory drug sulindac and differ in their ability to inhibit cyclooxygenase-2 (COX-2) enzyme function. Sulindac sulfide (the sulindac metabolite with COX-2 inhibitory function) demonstrated strong cell growth inhibition as measured by MTT and growth assays in UM-SCC-1 and SCC-25 cells, while sulindac sulfone had only moderate effect. Growth inhibition by sulindac sulfide was associated with a significant increase in percent G cells and activation of caspase-3. Sulindac sulfide induced expression of p21wafl/cipl in a dose-dependent fashion, decreased cyclin D1 protein levels, and increased Rb hypophosphorylation. p21waf1/cip1 protein levels increased without a significant increase in wild-type p53, suggesting that sulindac sulfide induces a p53-independent pathway regulating p2lwafl/ciP1 protein levels in SCCHN. Sulindac sulfide also induced dose-dependent expression of PPAR-gamma. In contrast, sulindac sulfone did not significantly alter apoptosis, cell cycle distribution or G1 checkpoint protein expression at doses below 200 microM. These results demonstrate the differential activity of sulindac metabolites and support the hypothesis that sulindac sulfide induced perturbations in SCCHN cellular proliferation could be regulated both by p21waf1/cip1-dependent cytostatic and caspase-dependent cytotoxic pathways.
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PMID:Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition. 1717 18

Tumor markers play an important role in the diagnosis of cancer. Cervical carcinoma and endometrial cancer are the most frequent diseases of the reproductive organs and their morbidity rates are constantly increasing. Many tumor markers may be used in the diagnosis and monitoring of endometrial and cervical carcinoma, for example CA 125, SCC-Ag, TPA, TPS, and CYFRA 21-1. New tumor markers useful in the early diagnosis and in monitoring the treatment and recurrence of the uterine cancer are still being sought. Investigations are underway on such substances as cytokines (e.g. M-CSF) and molecular markers of carcinogenesis (e.g. K-ras and p53).
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PMID:[Tumor markers useful in the diagnostics and monitoring of endometrial and cervical cancer]. 1736 80

In this study we show that deltaNp63alpha overexpression in primary human epidermal keratinocytes causes decreased cell proliferation and increased apoptosis. These changes are associated with increased levels of p21 and p27, decreased cyclin D1 and cyclin E levels, reduced mitochondrial membrane potential, and enhanced procaspase and poly(ADP-ribose) polymerase cleavage. Bcl-xS and Bax levels are increased and Bcl-xL level is reduced. p53 levels are increased in the deltaNp63alpha-expressing cells and p53 overexpression reproduces features of the deltaNp63alpha phenotype. Increased p53 expression results in reduced deltaNp63alpha, suggesting that p53 may negatively regulate deltaNp63alpha level. DeltaNp63alpha also induces apoptosis in HaCaT and SCC-13 cells, which encode inactive p53 genes, suggesting that the response is p53 independent in these cell lines. Both deltaNp63alpha and TAp63alpha reduce SCC-13 cell survival. These studies indicate that both deltaNp63alpha and TAp63alpha can negatively regulate keratinocyte survival.
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PMID:DeltaNp63alpha promotes apoptosis of human epidermal keratinocytes. 1739 28

It is reported that surveillance of serum p53 antibody (Ab) is a useful marker in detecting esophageal squamous cell carcinoma (ESCC). But there is little reported about prognostic significance of serum p53-Ab in postoperative patients with ESCC. The aim of this study is to evaluate the significance of preoperative serum p53-Ab as a marker of early recurrence after curative resection for ESCC. Enzyme-linked immunosorvent assay (ELISA) was used to analyze serum p53-Ab before treatment in 44 patients with ESCC. Carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC-Ag) were examined by immunoradiometric assay. The patients who were strongly positive and positive in serum p53-Ab were more likely to have early recurrence after curative resection than seronegative patients. There were no significant correlations between CEA, SCC-Ag positivity and early recurrence. We found that serum p53-Ab was useful to predict a risk of early recurrence after curative surgical resection for ESCC.
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PMID:Serum p53 antibody as a predictor of early recurrence in patients with postoperative esophageal squamous cell carcinoma. 1743 94

Celecoxib inhibits proliferation and induces apoptosis in human tumors, but the molecular mechanisms for these processes are poorly understood. In this study, we evaluated the ability of celecoxib to induce toxicity in head and neck squamous cell carcinomas (HNSCC) and explored the relationships between celecoxib-induced cell cycle inhibition and toxicity in HNSCC. Celecoxib inhibited the proliferation of UM-SCC-1 and UM-SCC-17B cells both in vitro and in vivo, accompanied by G(1) phase cell cycle arrest and apoptosis. Celecoxib induced p21(waf1/cip1) at the transcriptional level independent of wild-type p53 function, leading to decreased expression of cyclin D1 and hypophosphorylation of Rb, with subsequent marked downstream decreases in nuclear E2F-1 protein expression and E2F transactivating activity by luciferase reporter assay. Cell cycle phase-specific cytometric sorting showed that celecoxib induced clonogenic toxicity preferentially to cells within the S phase greater than G(1) and G(2) phases. Levels of p21(waf1/cip1) and cyclin D1 protein were reduced in the S phase compared with the G(1) and G(2) phases, suggesting a possible protective role for p21(waf1/cip1) expression in celecoxib toxicity. In conclusion, we show that celecoxib has marked antiproliferative activity against head and neck cancer cells through transcriptional induction of p21(waf1/cip1) and G(1) phase accumulation leading to S phase-specific clonogenic toxicity. We additionally show that a profound inhibition of nuclear E2F function provides a possible mechanism for this S phase-specific toxicity.
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PMID:Celecoxib toxicity is cell cycle phase specific. 1744 94

14-3-3 sigma has been a major G2/M checkpoint control gene and has demonstrated that its inactivation in various cancers occurs mostly by epigenetic hypermethylation, not by genetic change. This study investigated the methylation status and expression of the 14-3-3 sigma gene in 46 oral squamous cell carcinomas by methylation-specific polymerase chain reaction, reverse transcriptase-polymerase chain reaction, Western blotting and immunohistochemistry. Exons of the p53 gene were examined for mutations by sequencing analysis and CyclinD1 by immunohistochemistry. Methylation of the 14-3-3 sigma gene was detected in 13% (6/46) of the oral tumours, but not in corresponding adjacent non-malignant and normal gingival tissues. Intratumoural heterogeneity was found in the tumour tissues including three 14-3-3 sigma-methylated samples. Methylation of 14-3-3 sigma was detected in 3 SCC with p53 mutations and 3 with wild-type p53. Our major findings are: (a) methylation of 14-3-3 gene promoter is a rare event in oral cancer; (b) it is not always associated with 14-3-3 protein levels and there is no clear relationship between its methylation and p53 mutation; (c) loss of 14-3-3 sigma expression is associated with reduced CyclinD1 gene expression.
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PMID:Methylation and intratumoural heterogeneity of 14-3-3 sigma in oral cancer. 1778 41

The fragile histidine triad (FHIT), frequently lost in many cancers, was identified as a candidate tumor suppressor gene at chromosome 3p locus 14.2. Loss of the FHIT protein because of the alteration or loss of heterozygosity by genetic deletion occurs in a variety of epithelial tumors including head and neck cancer. However, the biological function of the FHIT protein is still unknown and its role in intrinsic cellular proliferation remains particularly controversial in preinvasive lesions and invasive tumors of the head and neck. To clarify the role of the FHIT protein in laryngeal squamous cell carcinoma (LSCC) and to examine whether the expression of FHIT could be a prognostic parameter for laryngeal carcinogenesis, we investigated the relationship between the expression of the FHIT protein, other tumor suppressor gene products (p53 and p16), the cellular proliferation marker (Ki-67) and the survival time of patients with LSCC. In our study, there were significant differences (p<0.05) in the expression of FHIT between low grade dysplasia and LSCC. Additionally, survival time analysis showed a significant correlation between the reduction of FHIT expression and the length of disease-free survival (p<0.05) in patients with T1-T2 N0 laryngeal carcinoma. However, we did not confirm a relationship between the expression of FHIT, the other tumor suppressor gene products (p53 and p16) or the cellular proliferation marker (Ki-67). In conclusion, we provided evidence that the reduction of FHIT levels may be a useful prognostic indicator for the clinical outcome of laryngeal SCC. Our findings indicated that FHIT utilizes a pathway independent of p53 and is involved in abnormal cell proliferation via the breakdown of G0-G1 arrest in the larynx and apoptosis during multistep carcinogenesis of the larynx.
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PMID:Clinicopathological significance of the fragile histidine triad transcription protein expression in laryngeal carcinogenesis. 1835 66

PGP9.5 is a controversial molecule from an oncologic point of view. We recently identified frequent methylation of PGP9.5 gene exclusively in primary head and neck squamous cell carcinoma (HNSCC), suggesting that it could be a tumor suppressor gene. On the other hand, PGP9.5 was reported to be overexpressed in a subset of human cancers presumably due to intrinsic oncogenic properties or as a result of transformation. To demonstrate that PGP9.5 possesses tumor suppressive activity, we examined forced expression by stable transfection of PGP9.5 in 4 HNSCC cell lines. Although all 4 cell lines demonstrated reduced log growth rates in culture after transfection, only 2 cell lines with wild type p53 (011, 022) demonstrated decreased growth in soft agar. In 2 cell lines with mutant p53 (013, 019), we observed no altered growth in soft agar and increased sensitivity to UV irradiation. We then tested for and found a high frequency of promoter methylation in a larger panel of primary tumors including HNSCC, esophageal SCC, gastric, lung, prostate and hepatocellular carcinoma. Our data support the notion that PGP9.5 is a tumor suppressor gene that is inactivated by promoter methylation or gene deletion in several types of human cancers.
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PMID:The role of PGP9.5 as a tumor suppressor gene in human cancer. 1851 40

Genetic alteration of p53 is a significant determining factor in the carcinogenesis. The loss of function, mutant p53 can possess a dominant negative effect on wild-type p53 and may also exert gain-of-function activity. It is, however, not clear how p53 functional status due to various types of mutation results in outcome of patients with oral cancer. A total of 60 oral SCC samples were subjected to yeast functional assay that screens human p53 function in yeast, and sequencing for determination of p53 mutations. The detected mutants were further investigated for their dominant negative activity using a yeast-based transdominance assay that tests dominant negative activity of a mutant p53 over wild-type p53 by coexpressing the mutant and wild-type p53 in a yeast transcriptional reporter system. p53 mutation was found in 42 out of 60 of which 10 (24%) exhibited dominant negative activity and 32 (76%) without dominant activity (recessive mutation). The remaining 18 (30%) were considered to have wild-type p53. The patients with dominant negative mutation had significantly shorter disease-free survival than patients with no mutation (log-rank test, p<0.001) and those with a recessive mutation (p<0.016). There were slight significant differences in disease-free survival were found between the patients with tumours harbouring a recessive p53 mutation and those with tumours harbouring a wild-type p53 (p<0.038). The presence and absence of a dominant negative p53 mutation may thus provide a predictor of early recurrence in oral SCC patients.
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PMID:Presence of dominant negative mutation of TP53 is a risk of early recurrence in oral cancer. 1855 92


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