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

Gastric cancer, like all cancers, is considered to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumour suppressor loss. More recently, the role of epigenetic change as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes has emerged in many cancer types. The study of DNA methylation changes in gastric cancer has now provided additional clues into the pathogenesis of the disease. E-cadherin as a metastases suppressor is mutationally inactivated in both familial and sporadic forms of gastric cancers. Evidence now suggests that the transcriptional silencing of E-cadherin gene by promotor methylation plays a crucial role in the development and progression of gastric malignancies. In order to further analyze the role of E-cadherin gene promotor methylation in gastric carcinogenesis and progression, we performed the studies of promoter methylation status and protein expression of E-cadherin gene in associated progression stages of gastric cancer. DNA were extracted from the paraffin embedded gastric specimens of dysplasia(23 cases), early cancer (20 cases) and advanced cancer (20 cases). Methylation specific PCR and immunohistochemistry were used to analyze the promoter methylation status and the protein expression level of E-cadherin gene. Our results showed that E-cadherin promoter methylation occurred in all stages of gastric precancerous lesion and carcinogenesis, which suggests E-cadherin promotor methylation is an important event during gastric carcinogenesis and progression. The positive rate of E-cadherin promotor methylation in dysplasia, early gastric cancer and advanced gastric cancer was 78.3%, 80% and 90% respectively. There were significant differences between experimental groups and control group(30%), P < 0.05, but no significant differences among experimental groups, P > 0.05. All of advanced gastric cancer examined were completely E-cadherin protein-negative by immunohistochemistry. Fourteen of 20 early gastric cancer were E-cadherin-negative. And 23 dysplasia were all E-cadherin-positive. Thirty-one of 34(91%) of the E-cadherin-negative tumours had promotor methylation. This result indicated the downregulation expression of E-cadherin was associated with promotor methylation in early and advanced gastric cancer (P < 0.01).
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PMID:[Studies of promoter methylation status and protein expression of E-cadherin gene in associated progression stages of gastric cancer]. 1277 96

Association of infection with papillomavirus and dysplasia of the cervix uteri has been firmly established. There are only few cervical cancers where no HPV DNA is detectable. The mechanism of epithelial cell immortalization by interaction with tumour suppressor genes p53 and pRb by viral oncogenes E6 and E7 is elucidated. Progression of the HPV infected cell to a malignant phenotype involves further modification of host gene expression and/or mutations. The appearance of chromosomal aberrations can lead to mutational inactivation or loss of tumour suppressor genes (TSG), activation and amplification of oncogenes, with importance for the process of carcinogenesis. Oncogene amplification, with exception of few reports, seems not to be a major mechanism in cervical carcinogenesis. In contrast, cytogenetic and loss of heterozygosity (LOH) results from CIN and invasive cancer demonstrate alterations at specific chromosomal regions, pointing at localisation of TSG. Genetic alterations at chromosomes 3p, 6p, 1lq were frequently found early in tumour development Primary invasive carcinoma showed additional allelic losses at chromosome arms 6q, 17p and 18q. Useful biological diagnostic and prognostic markers for high-risk HPV infection and malignant progression may be p16NK4 p27Kip, and NET-I/C4.8. Putative senescence genes relevant for HPV-induced carcinogenesis are localized on chromosomes 2, 4 and 10. Genes for Telomerase suppression are presumably located on chromosomes 3, 4 and 6. Natural immune responses to HPV infection exist Therefore, immune therapy is an attractive possibility for prevention and therapy of HPV infection. To date, vaccine development has reached clinical evaluation. Prophylaxis aims at the induction of virus neutralizing antibodies to capsid proteins. Virus-like particle vaccines are currently tested in clinical trials. Due to the long lag period between infection and clinical manifestation trials will take a long time until conclusive results are obtained. Mandatory expression of viral and perhaps certain cellular genes in infected epithelial and tumour cells offers targets for therapeutic approaches. Since most dysplasia clears spontaneously the viral infection is immunogenic to some extent. However, in some individuals the immune response has to be stimulated by vaccination in order to be effective. Several strategies are being tested in clinical trials and others are in preclinical development The task will be to circumvent immunosuppressive features of the HPV infected cells.
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PMID:HPV induced cervical carcinogenesis: molecular basis and vaccine development. 1279 44

The purpose of this study was to investigate the relationship between epithelial dysplasia unstained with iodine and the expression of proliferating cell nuclear antigen (PCNA) and/or tumour suppressor gene (p53) and the existence of glycogen. Thirty cases of squamous cell carcinomas arising from the buccal mucosa and floor of the mouth were examined. Iodine unstained areas were diagnosed histopathologically as mild, moderate or severe epithelial dysplasia. Normal oral mucosa stained with iodine was used as a control group. There was no histochemical difference in the distribution or ratio of PAS-positive cells between the control and the mild epithelial dysplasia groups, however PAS stained areas of the moderate and the severe dysplasia groups were significantly decreased. Ultrastructurally, glycogen granules were not recognized in the moderate or severe dysplastic epithelia. Immunoreactive ratios of PCNA and p53 in the moderate and severe dysplastic groups were significantly higher than those of the control and the mild dysplasia groups. The positive ratio of PCNA was higher than that of p53, although the immunostaining patterns of PCNA- and p53-positive cells were quite similar. These results suggest that mild dysplastic epithelia that are stained with iodine may be in the category of normal epithelia, whereas both moderate and severe dysplasia that are un-stained with iodine may be suspected of malignant lesions.
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PMID:Cell proliferation and tumour suppressor gene expression in iodine unstained area surrounding oral squamous cell carcinoma. 1469 Jun 63

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

The DBCCR1 gene at chromosome 9q33 has been identified as a candidate tumour suppressor, which is frequently targeted by promoter hypermethylation in bladder cancer. Here, we studied the possible involvement of DBCCR1 in the development of oral squamous cell carcinoma. DNA from 34 tumours was examined for loss of heterozygosity (LOH) at three markers surrounding DBCCR1 and for hypermethylation of the DBCCR1 promoter, using methylation-specific PCR and methylation-specific melting-curve analysis. LOH was found in 10 of 31 cases (32%), and DBCCR1 hypermethylation was present in 15 of 34 cases (44%). Hypermethylation of DBCCR1 was also present in three of seven epithelial tissues adjacent to the tumours, including two hyperplastic and one histologically normal epithelia. Furthermore, of four oral leukoplakias with dysplasia, one showed LOH at 9q33 and two showed DBCCR1 hypermethylation. These data suggest that LOH at 9q33 and hypermethylation of the DBCCR1 promoter are frequent and possibly early events in oral malignant development.
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PMID:Loss of heterozygosity at 9q33 and hypermethylation of the DBCCR1 gene in oral squamous cell carcinoma. 1522 71

The incidence of cutaneous malignant melanomas is growing faster than that of any other cancer and therefore posing a major heath threat worldwide. In melanocytic skin tumours, the feasibility of correlating a specific pathological stage with a corresponding genetic alteration provides a remarkable opportunity to study the multistep tumorigenesis model. This multistep melanoma tumorigenesis is best described as a continuum of transformation of the melanocytes, melanocytic dysplasia, and melanoma formation. These steps involve genotypic alterations including loss of tumour suppressor genes, microsatellite instability, and alterations of the mismatch repair system. This review seeks to examine melanoma tumorigenesis based on these genetic changes.
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PMID:Genetic pathways to melanoma tumorigenesis. 1528 Mar 98

Idiopathic ulcerative colitis (IUC) patients have higher incidence of dysplasia and malignancy. Close follow-up with biopsy at regular interval is mandatory. The study was done to correlate incidence of atypical epithelium, goblet cell hyperplasia (GCH) and disease duration (DD) with Ki67, AgNOR and p53 expression in IUC with disease for 5 or more years. Ki67 and AgNOR are good indicators of cellular proliferation and p53 tumour suppressor protein is a marker for neoplastic cell. Of 130 cases studied, 40 cases showed atypical epithelium and were selected for further study. DD in these 40 cases ranged from 60 to 228 months. All had GCH and showed histological features of chronicity. Low-grade dysplasia (LGD) was seen in 15 cases, indefinite for dysplasia (ID) in 8 and inflammatory atypia in 17 cases. Disease duration showed no influence in the type of atypical epithelium. A positive staining of lining epithelium by Ki67 and p53 was not restricted to dysplasia. LGD and ID showed stronger p53 nuclear staining. AgNOR appeared to be a more sensitive marker than Ki67. GCH showed a positive correlation with DD and AgNOR index. p53 expression correlated positively with goblet cell hyperplasia. Conclusion- goblet cell hyperplasia could indicate presence of epithelial cell dysplasia.
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PMID:Goblet cell status in idiopathic ulcerative colitis--implication in surveillance program. 1547 Nov 16

Premalignant conditions affect the larynx. Dysplasia can progress in severity resulting in cancer depending on many clinical, pathological and molecular factors. The purpose of this study was to examine the expression of the p21 and p27 cyclin-dependent kinase inhibitors and p53 tumour suppressor gene in dysplasia of the larynx. A total of 114 cases of untreated dysplasia were selected from the archives of the University of Newcastle. p21, p27 and p53 immunohistochemistry was performed and the cases followed up. Twenty-eight dysplasias (24%) subsequently developed into cancers. Expression of the molecular factors studied was not associated with cancer progression. p53 expression was associated with smoking (P = 0.005). In contrast, grade of dysplasia was significantly associated with cancer risk (odds ratio 6.7; P = 0.0001). The majority (75%) of cancers were detected within 12 months of dysplasia being diagnosed.
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PMID:Molecular markers in dysplasia of the larynx: expression of cyclin-dependent kinase inhibitors p21, p27 and p53 tumour suppressor gene in predicting cancer risk. 1553 63

Del (9q) is a recurrent cytogenetic abnormality in acute myeloid leukaemia (AML). We report an analysis of 81 patients with del(9q) as a diagnostic karyotypic abnormality entered into the Medical Research Council AML trials 10, 11 and 12. Patients were divided into three groups: (i) Sole del (9q), 21 patients; (ii) Del(9q) in association with t(8;21), 29 patients; (iii) Del(9q) in association with other cytogenetic abnormalities, 31 patients. Sole del(9q) was associated with a characteristic bone marrow phenotype at diagnosis: a single Auer rod was found in all cases examined. There was also an association with erythroid dysplasia (74%) and granylocytic lineage vacuolation (90%). The incidence of all three of these features was significantly higher (P < 0.05) in the sole del(9q) group compared with control cases lacking del(9q). The overall survival (OS) of all 81 patients was compared with a control group of 1738 patients with normal cytogenetics entered in the same trials over the period of investigation. The 5-year OS for patients with del(9q) was 45%, compared with 35% for the control group (P = 0.09). Patients with del(9q) in association with t(8;21) had a 5-year OS of 75%, which was significantly better than the groups with either sole del(9q) (40%) and del(9q) with other abnormalities (26%; P = 0.008). Karyotyping indicated a common area of deletion in the region 9q21-22, which was present in 94% of cases. It is likely that the deletion of single or multiple tumour suppressor genes located in this region may underlie the pathogenesis of del (9q) AML.
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PMID:Del (9q) AML: clinical and cytological characteristics and prognostic implications. 1615 71

Tumours of the gastrointestinal (GI) tract, of which 70% arise in the colorectum, are a major cause of morbidity and mortality worldwide. Transformation from normal to malignant mucosa is a multistep process involving specific gene mutations and is called the adenoma-carcinoma sequence. Histologically, adenomas are of three types (tubular, tubulovillous and villous) and the extent of mucosal cellular abnormality of three grades (mild, moderate and severe). Cellular proliferation is a marker of malignant potential in many tissues. In the colon, cellular proliferation is partly controlled by the CDX-2 gene, a homeobox gene expressed in differentiated cells of the intestine that has proto-oncogenic potential in murine models. In the stomach, CDX-2 is expressed in intestinal metaplasia and decreasing expression through tumourogenesis shows its tumour suppressor potential. Down-regulation in colorectal cancer cell lines is also observed. This is a retrospective study of colorectal adenomas, and haematoxylin and eosin (H&E) and immunocytochemical staining for CDX-2 and MIB-1 (a cell proliferation marker) are performed on each case. Comment is made on the morphological features (adenoma type and dysplasia severity) and the grade of CDX-2 and MIB-1 expression. This study showed that dysplasia severity is linked to cellular proliferation (P=0.011) but adenoma type was not (P=0.54). CDX-2 was not linked to the morphological features discussed (P=0.11 and P=0.16) and CDX-2 and MIB-1 expression showed no correlation. Increased cell proliferation (MIB-1 expression) was seen in increasingly dysplastic adenomatous lesions of the colorectum. CDX-2 had no link to morphological features or cell proliferation of the dysplastic mucosa.
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PMID:CDX-2 and MIB-1 expression in the colorectum: correlation with morphological features of adenomatous lesions. 1687 98


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