Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Statistics rate colorectal adenocarcinoma as the most common cause of cancer death on exclusion of smoking-related neoplasia. However, the reported accumulation of genetic lesions over the adenoma to adenocarcinoma sequence cannot wholly account for the neoplastic phenotype. Recently, heritable, epigenetic changes in DNA methylation, in association with a repressive chromatin structure, have been identified as critical determinants of tumour progression. Indeed, the transcriptional silencing of both established and novel tumour suppressor genes has been attributed to the aberrant cytosine methylation of promoter-region CpG islands. This review aims to set these epigenetic changes within the context of the colorectal adenoma to adenocarcinoma sequence. The role of cytosine methylation in physiological and pathological gene silencing is discussed and the events behind aberrant cytosine methylation in ageing and cancer are appraised. Emphasis is placed on the interrelationships between epigenetic and genetic lesions and the manner in which they cooperate to define a CpG island methylator phenotype at an early stage in tumourigenesis. Finally, the applications of epigenetics to molecular pathology and patient diagnosis and treatment are reviewed.
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PMID:Methylation and colorectal cancer. 1156 97

Dysregulation of CpG-methylation is a common feature of many human cancers and tumour suppressor genes can be silenced by hypermethylation. Recently, 2 methyl-CpG-binding domain proteins have been linked to gene inactivation by their ability to recruit co-repressors and HDAC-activity to methylated gene promoters. Here, we have analysed mRNA expression of these genes, MeCP2 and MBD2, in a wide variety of primary human tumours. In solid tumours, expression levels of MBD2 (57/71) and MeCP2 (64/71) were significantly reduced in the majority of primary tumours as detected by quantitative real-time RT-PCR. Western blot analyses of MeCP2 in matched tumour-normal samples of patients with non-small-cell lung cancer (NSCLC) indicated reduced protein in a significant percentage of patients. In acute myelogenous leukaemia (n = 26), expression levels were only slightly reduced and did not differ between samples analysed at diagnosis or at the time of relapse. In early-stage NSCLC (n = 70) expression of MeCP2 and MBD2 was significantly lower in squamous cell carcinoma than in adenocarcinoma or large cell carcinoma (P = 0.03 and P = 0.01). To further elucidate the mechanisms of gene regulation, we analysed MeCP2 and MBD2 regulation during haematopoietic differentiation. No significant changes in MeCP2 or MBD2 expression were found when NB4 cells were differentiated toward granulocytes suggesting that neither differentiation nor cell cycle status were relevant for the reduced expression of these genes in human cancer. In conclusion, the significant loss of MeCP2 and MBD2 expression in human cancers suggests a potential role of this phenomenon in the development of solid human tumours.
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PMID:Loss of expression of HDAC-recruiting methyl-CpG-binding domain proteins in human cancer. 1171 Aug 31

The p53, a tumour suppressor gene, is the most commonly mutated gene human cancer. In this study, we performed immunohistochemical investigations of the expression of p53 protein in hyperplastic endometrium and adenocarcinoma. Positive immunostaining was detected in 7 (30%) cases of invasive adenocarcinoma, 2 (12%) cases of simple hyperplasia with atypia and 2 (14%) cases of complex hyperplasia with atypia. In simple and complex hyperplasia without atypia staining was seen in occasional cells. The results suggested that endometrial hyperplasia is not always accompanied by p53 protein accumulation, hence its expression is not an early exponent of the neoplastic process.
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PMID:Patterns of immunohistochemical staining for p53 expression in hyperplastic endometrium and adenocarcinoma. 1182 Jun 4

Prostatic adenocarcinoma (CaP) is the most common, non-cutaneous malignancy and the second-leading cause of cancer death in men. The disease has two distinct phases: the androgen-dependent phase, which can be treated effectively with androgen ablation therapies, and the androgen-independent phase, for which there is no effective life-prolonging therapy. An estimated 32,000 men will die this year from androgen-independent, metastatic CaP. Efforts to understand the metastatic progression of CaP and the emergence of androgen-independent disease have begun to illuminate the molecular events involved. Recent work suggests that CaP progression to androgen-independent, metastatic disease involves a dampened apoptotic response, a release from the cell cycle block that initially follows androgen withdrawal and a shift from dependence on paracrine-derived growth and survival factors to autonomous production of these key proteins. Functional loss of the tumour suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) and subsequent activation of the AKT pathway, have been prominently implicated in the progression of CaP to androgen-independence. Activation of the AKT pathway can suppress the apoptotic response, undermine cell cycle control and selectively enhance the production of key growth and survival factors. Though many proteins and intracellular signalling pathways can influence these biological processes, activation of the AKT pathway may be a particularly potent signal involved in CaP progression to androgen-independence and therefore presents a series of potential targets for therapy of advanced androgen-independent CaP.
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PMID:Emerging targets in the AKT pathway for treatment of androgen-independent prostatic adenocarcinoma. 1190 76

Although most colorectal cancer develops based on the adenoma-adenocarcinoma sequence, morphologically, colorectal cancer is not a homogeneous disease entity. Generally, there are two distinct morphological types: polypoid and ulcerative colorectal tumours. Previous studies have demonstrated that K-ras codon 12 mutations are preferentially associated with polypoid growth of colorectal cancer; however, little is known about the molecular mechanism that determines ulcerative growth of colorectal cancer. beta-catenin complex plays a critical role both in tumorigenesis and morphogenesis. We examined the differential expression of beta-catenin and its related factors among different types of colorectal cancer in order to determine any relationship with gross tumour morphology. Immunohistochemical staining of beta-catenin, E-cadherin and MMP-7 was performed on 51 tumours, including 26 polypoid tumours and 25 ulcerative tumours. Protein truncation tests and single-strand conformational polymorphism for mutation of the adenomatous polyposis coli tumour suppressor gene, as well as single-strand conformational polymorphism for the mutation of beta-catenin exon 3 were also done. Nuclear expression of beta-catenin was observed in 18 out of 25 (72%) cases of ulcerative colorectal cancer and seven out of 26 (26.9%) cases of polypoid colorectal cancer. A significant relationship of nuclear beta-catenin expression with ulcerative colorectal cancer was found (P<0.001). However, this finding was independent of adenomatous polyposis coli tumour suppressor gene mutation and E-cadherin expression. Together with previous data, we propose that different combinations of genetic alterations may underlie different morphological types of colorectal cancer. These findings should be taken into consideration whenever developing a new genetic diagnosis or therapy for colorectal cancer.
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PMID:Nuclear beta-catenin expression is closely related to ulcerative growth of colorectal carcinoma. 1195 60

Fragile histidine triad (FHIT) is a tumour suppressor gene, which is altered in a variety of epithelial tumours, including lung cancer. Biochemical and functional pathways of its tumourigenicity are not yet understood. Its role in tumour proliferation is particularly controversial. The purpose of this study was to correlate the expression of FHIT protein in nonsmall cell lung cancer (NSCLC) with tumour proliferation as estimated by Ki-67 antigen and with p53, a suppressor gene. FHIT, Ki-67 and p53 expression were evaluated by immunohistochemistry in 119 resected NSCLC. Altogether, 58 tumours were negative (expression <10%) for FHIT. The median expression in tumours was 15% positive cells, in comparison with 100% in normal matched lung tissue. The expression was as strong as in normal tissue in only 19 cases. FHIT expression was significantly lower in squamous cell carcinoma (SCC) (5%) than in adenocarcinoma (ADC) (64%). The median expression of Ki-67 was 20% and 69% of tumours were positives (expression >10%). Ki-67 expression was significantly higher in SCC (33.3%) than in ADC (10%). The loss of FHIT protein was not correlated with the expression of p53 (median: 7.5%, 58% of positive tumours for a cut-off of 10% of positive cells) or Ki-67. But percentage of labelled cells for p53 and Ki-67 were significantly correlated. The results suggest that for fragile histidine triad, the pathway of tumourigenesis is independent of p53 and of tumoural proliferation, as reported previously in vitro.
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PMID:Fragile histidine triad protein expression in nonsmall cell lung cancer and correlation with Ki-67 and with p53. 1276 16

Allelic imbalance (AI) studies on chromosome 17 (C17) in Barrett's oesophageal adenocarcinoma (BOA) tumours strongly suggest that a minimally deleted region on C17p harbours a BOA-associated gene with tumour suppressor function. This deleted region, designated minimal region III (MRIII), lies between the two microsatellite markers D17S1852 and D17S954. Computational sequence analysis techniques, BLAST and NIX, were used to assemble a physical map of MRIII, consisting of three overlapping bacterial artificial chromosome (BAC) clones, 297N7, 963H4 and 795F17, from the RPCI-11 library. The 270 kb genomic sequence of MRIII was analysed using the computational gene prediction methods NIX and TAP to identify putative BOA genes. A transcript map of MRIII has been generated and contains 25 candidate BOA genes, four of which are the named genes MYH3, SCO1, x006 and MAGOH-LIKE. The other candidates consist of seven genes predicted by TAP with associated ESTs identified by NIX, two genes predicted by TAP alone and 12 genes/ESTs (or pairs of ESTs) identified by NIX alone. No disease-specific mutations were identified in x006 or MAGOH-LIKE, although expression analysis of these genes suggests that they may show alternative splicing or be altered epigenetically or in regulatory regions in oesophageal cancer.
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PMID:Physical and transcript map of the minimally deleted region III on 17p implicated in the early development of Barrett's oesophageal adenocarcinoma. 1282 48

Hypermethylation of cytosines in CpG-rich islands of the promoter regions of regulatory genes has been discovered as a common mechanism of gene silencing during carcinogenesis. We analysed 64 primary lung carcinomas for promoter methylation of the tumour suppressor genes (TSGs) p16 (p16(INK4a)/CDKN2A) and p14 (p14(ARF)) by methylation-specific PCR, in order to evaluate aberrant methylation as a potential biomarker for epigenetic alterations in tobacco-related lung cancer. Methylation of p16 was observed in 34% (22/64) of the lung tumours examined. In particular, p16 methylation occurred in nonsmall cell lung cancer (NSCLC) only, with 41 % (22/54) of the tumours being positive. The highest frequency was found in large cell carcinoma (5/7, 71%), followed by adenocarcinoma (9/25, 36%) and squamous cell carcinoma (7/21, 33%). Methylation of the p14 gene was less frequent in lung cancer (4/52, 8%). When association with tobacco smoking was analysed, 42% (21/50) of NSCLC from ever smokers exhibited p16 methylation. Interestingly, the analysis revealed a significantly higher risk of p16 methylation in former smokers as compared to current smokers [odds ratio (OR) 5.1; 95% confidence interval (CI) 1.3-22]. The difference was retained after adjustment for age (OR 3.7; 95% CI 0.9-17). The promoter methylation results were then combined with data on genetic alterations determined previously in the same set of tumours. This data similarly showed that p16 methylation in parallel with p53 gene mutation or p14 methylation occurred more frequently in former smokers than in current smokers (44% vs. 14%; P = 0.035). Taken together, our data suggest that analysis of promoter methylation in TSGs may provide a valuable biomarker for identification of groups with an elevated risk of cancer, such as smokers and ex-smokers.
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PMID:Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer. 1291 69

Defective DNA mismatch repair results from genetic or epigenetic alterations that most frequently inactivate the genes hMLH1 and hMSH2. This is thought to promote tumourigenesis by accumulation of mutations in oncogenes and tumour suppressor genes. This pathway, first reported in colon cancer, has been recently demonstrated in a subgroup of sporadic pancreatic adenocarcinomas. Intraductal papillary-mucinous neoplasms of the pancreas are a special type of pancreatic tumours, characterised by a spectrum of morphological changes from mild to moderate and to non-invasive, and they may associate with adenocarcinoma. An immunohistochemical study of hmlh1 and hmsh2 protein expression was performed on 26 intraductal papillary-mucinous neoplasms. All tumours showed nuclear expression of hmlh1 and hmsh2 proteins. There were two distinctive patterns of protein expression on the basis of the location of cells expressing these markers: the "normal" pattern, observed mainly in adenoma and rarely in intraductal papillary-mucinous neoplasms with moderate dysplasia and the "dysplastic" pattern, frequently encountered in moderate dysplasia neoplasms, non-invasive and invasive carcinomas. These findings suggest that defective DNA mismatch repair, due to inactivation of hMLH1 and hMSH2, does not play a significant role in the pathogenesis of intraductal papillary-mucinous neoplasms of the pancreas. Two patterns of protein expression were observed and were correlated with the progression of dysplasia in intraductal papillary mucinous neoplasms.
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PMID:Correlation between patterns of DNA mismatch repair hmlh1 and hmsh2 protein expression and progression of dysplasia in intraductal papillary mucinous neoplasms of the pancreas. 1476 May 34

Invasive parenchymal-type lung adenocarcinoma develops from atypical adenomatous hyperplasia (AAH), through an intermediate in situ stage of bronchioloalveolar carcinoma (BAC). We examined the expression of the putative tumour suppressor gene product Fhit, cell adhesion molecules CD44v6, E-cadherin and beta-catenin, and matrix metalloproteinase 2 and its inhibitor, TIMP-2, in a range of AAH lesions, BACs and invasive adenocarcinomas, to determine the changes in molecular expression associated with this form of neoplastic progression. Sections of formalin-fixed wax-embedded archival tissue were stained by standard Immunohistochemical techniques and scored semi-quantitatively, resulting in a grading of negative/low- or high-level staining. Fhit protein was retained at high levels in over 90% of AAH and 83% of BAC, but was found in only 6% of stromally invasive tumours (p < 0.0001). CD44v6 staining was high-level in 64% of AAH but fell to 26% in stromally invasive tumour (p = 0.007). E-cadherin and beta-catenin showed the opposite, with more high-level staining as adenocarcinoma developed (p < 0.001). High-level MMP-2 and TIMP-2 expression was relatively infrequent in AAH (32% and 40% respectively), rose in BAC (89% each) but fell in stromally invasive tumour (31% and 17% respectively) (p < 0.01). Unlike in central bronchial carcinogenesis, loss of Fhit expression is a relatively late event in this putative progression of lung adenocarcinogenesis, and has potential as a surrogate marker of invasion, which could be of value in screening patients for lung cancer. Loss of CD44v6 expression follows the convention of falling adhesion molecule expression as malignancy develops. Increased expression of E-cadherin and beta-catenin may reflect increased cell-cell contact as tissue architecture changes in the transition from AAH to adenocarcinoma. Loss of MMP-2 and TIMP-2 in stromally invasive tumour may reflect a particular role for MMP-2 at the BAC stage, with later down-regulation of this particular enzyme.
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PMID:Expression of Fhit, cell adhesion molecules and matrix metalloproteinases in atypical adenomatous hyperplasia and pulmonary adenocarcinoma. 1514 78


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