Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gap junctional intercellular communication (GJIC) has been reported to be markedly reduced in human mesothelioma tumour cell lines compared with primary mesothelial cells. Immunofluorescence stainings have shown that the gap junction protein connexin43 (Cx43) is expressed in both malignant and normal mesothelial cells. In this study the mRNA expression of Cx43 and three different connexins--Cx37, Cx40 and Cx45, which are highly expressed in lung tissue--was investigated in eight human mesothelioma cell lines, and in human primary mesothelial cells from several donors. The expression of the intercellular adhesion molecules A-CAM (N-cadherin) and L-CAM (E-cadherin) was studied at the protein level. No mRNA expression of Cx37, Cx40 or Cx45 in either mesothelioma tumour cells or the primary mesothelial cells was detected. Cx43 was expressed at both the mRNA and the protein level, in seven out of eight mesothelioma cell lines, as well as in all the primary mesothelial cell cultures. The well as in all the primary mesothelial cell cultures. The intercellular adhesion molecule A-CAM was expressed at the cell-cell borders in six out of seven mesothelioma cell lines, as well as in normal mesothelial cells. No expression of L-CAM was observed in these cells. The results suggest that Cx43 and A-CAM are the major proteins in gap and adherens junctions respectively in human mesothelial cells. Most mesothelioma tumour cell lines with markedly reduced GJIC still express both Cx43 and A-CAM. Only one of our mesothelioma tumour cell lines severely deficient in GJIC lacks both the gap junction protein Cx43 and the cell adhesion molecule A-CAM.
Carcinogenesis 1994 Nov
PMID:Expression of cell adhesion molecules and connexins in gap junctional intercellular communication deficient human mesothelioma tumour cell lines and communication competent primary mesothelial cells. 795 25

We have analyzed the expression of E- and N-cadherins in benign, borderline, and maligant ovarian tumors, and we have correlated the pattern of cadherin expression with the standard clinicopathological parameters. An immunohistochemical technique has been applied to formalin-fixed, paraffin-embedded samples of 20 benign cystic tumors, 20 borderline tumors, and 20 cancers. Expression of E- and N-cadherins immunostaining were compared with the histological type, degree of histological differentiation, International Federation of Gynecology and Obstetrics (FIGO) stage, presence of ascites, occurrence of recurrence, and survival. E-cadherin was homogeneosuly expressed in benign tumors but was heterogeneously expressed or undetectable in most borderline and malignant tumors. In contrast, N-cadherin was detected in most benign and borderline tumors but was absent or heterogeneous in most carcinomas. The difference of expression of E-cadherin and N-cadherin between the three groups of ovarian tumors was statistically significant (respectively, P = .03 and P < .001). In ovarian carcinoma, patients with negative E-cadherin staining present a significantly shorter survival. No correlation was found between cadherin expression and clinicopathological parameters in borderline tumors. Our results suggest that alterations in E-cadherin and N-cadherin expressions are differentially involved in ovarian carcinogenesis and may have diagnostic and prognostic values.
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PMID:Expression of cadherins in benign, borderline, and malignant ovarian epithelial tumors: a clinicopathologic study of 60 cases. 926 28

E(pithelial)-cadherin and N(eural)-cadherin are transmembrane cell-cell adhesion molecules, belonging to the subfamily of classical cadherins. The expression of E- and N-cadherin is spatiotemporally regulated and associated with a variety of normal morphogenetic events. The expression of E- and N- cadherin is also involved in carcinogenesis. E-cadherin functions as a tumor-suppressor. N-cadherin, however, is associated with cancer progression. The study of the expression pattern of E- and N-cadherin in the normal and tumorous eye is the aim of our research.
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PMID:Cadherin expression in the eye. 1176 62

Epithelial-mesenchymal transition (EMT) involving down-regulation of E-cadherin is thought to play a fundamental role during early steps of invasion and metastasis of carcinoma cells. The aim of our study was to elucidate the role of EMT regulators Snail, SIP1 (both are direct repressors of E-cadherin), and Twist (an activator of N-cadherin during Drosophila embryogenesis), in primary human gastric cancers. Expression of Snail, SIP1, and Twist was analyzed in 48 gastric carcinomas by real-time quantitative RT-PCR in paraffin-embedded and formalin-fixed tissues. The changes of expression levels of these genes in malignant tissues compared to matched non-tumorous tissues were correlated with the expression of E- and N-cadherin. From 28 diffuse-type gastric carcinomas analyzed reduced E-cadherin expression was detected in 11 (39%) cases compared to non-tumorous tissues. Up-regulated Snail could be found in 6 cases with reduced or negative E-cadherin expression. However, there was no correlation to increased SIP1 expression. Interestingly, we could detect abnormal expression of N-cadherin mRNA in 6 cases, which was correlated with Twist overexpression in 4 cases. From 20 intestinal-type gastric cancer samples reduced E-cadherin expression was found in 12 (60%) cases, which was correlated to up-regulation of SIP1, since 10 of these 12 cases showed elevated mRNA levels, whereas Snail, Twist, and N-cadherin were not up-regulated. We present the first study investigating the role of EMT regulators in human gastric cancer and provide evidence that an increase in Snail mRNA expression is associated with down-regulation of E-cadherin in diffuse-type gastric cancer. We detected abnormally positive or increased N-cadherin mRNA levels in the same tumors, probably due to overexpression of Twist. SIP1 overexpression could not be linked to down-regulated E-cadherin in diffuse-type tumors, but was found to be involved in the pathogenesis of intestinal-type gastric carcinoma. We conclude that EMT regulators play different roles in gastric carcinogenesis depending on the histological subtype.
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PMID:Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. 1241 34

A frequent genetic alteration found in premalignant stages of pancreatic adenocarcinoma is K-ras oncogene point mutation. The mechanistic basis for the inability of K-ras mutation to transform pancreatic ductal cells is unclear, although cooperating events with p16 inactivation, p53 mutation, and SMAD 4 mutation are recognized to be necessary. We have generated a novel mouse model in which the cytokeratin 19 promoter, specifically active in pancreatic ductal cells but not other cell types of the pancreas, is fused to mutant K-ras. This is of direct relevance to human pancreatic cancer because premalignant lesions are found specifically in ductal cells. There is dramatic periductal lymphocytic infiltration in the pancreata of transgenic mice, predominantly CD4+ T lymphocytes, which may act as an adaptive immune response to activated ras-mediated signaling. In addition, gene array analysis reveals an induction of N-cadherin in transgenic mice pancreatic ductal cells, the significance of which relates to promotion of cell adhesion and deterrence of cell migration. Apart from these important biological considerations, there is parallel activity of the cytokeratin 19 promoter in the stem cell region of the gastric epithelium, namely in mucous neck cells. Activated K-ras in this context causes mucous neck cell hyperplasia, a precursor to gastric adenocarcinoma. There is concomitant parietal cell decrease, which is a key step toward gastric adenocarcinoma. Taken together, we have defined how mutant K-ras signaling modulates important molecular events in the initiating events of pancreatic and gastric carcinogenesis.
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PMID:The mutant K-ras oncogene causes pancreatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in transgenic mice. 1272 9

Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial-mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during lung cancer progression are still not well understood. We have used a rat model for multistep lung carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, alpha-catenin and beta-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. alpha- and beta-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear beta-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat lung carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell-cell adhesion molecules are an early event in lung carcinogenesis, while EMT occurs at a later stage.
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PMID:Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis. 1519 14

Aberrant expression of some tumour suppressor genes and oncogenes by thymocytes had been involved in the development of primary thymic lymphomas induced by gamma-irradiation, but genetic alterations affecting critical genes expressed by stromal cells have not been yet explored. This paper analyzes a series of such tumours induced in C57BL/6J and in F1 hybrids of BALB/c and C57BL/6J mouse strains. As expected, hystopathological analyses revealed profound disorganizations within the thymus with a poor demarcation of the cortical and medullar areas. Immunological and quantitative on-line RT-PCR analyses confirm that E-cadherin (Cdh1) is essentially expressed by stromal cells of the thymus, while evidencing that the expression of this gene is significantly reduced in all tumours. In addition, and contrary to what one would expect, N-cadherin (Cdh2) that is exclusively expressed by stromal cells is likewise down-regulated in most of the thymic lymphomas. Although hypermethylation of the promoter region appears to be involved in the inactivation of Cdh2 in all tumours, additional epigenetic mechanisms mediated by repressors such as Snai1 may also play a role in Cdh1 silencing. These results represent the first reported case for tumour-associated gene alterations occurring not in the tumour cells per se, but in the stromal cells of primary thymic lymphomas. Additionally, since the expression of both genes is significantly up-regulated after a single high dose of gamma-radiation, but remained unchanged in treated thymic-lymphoma-free-mice, epigenetic down-regulation of E- and N-cadherin appears to occur concomitantly with the progression towards the most advanced stages of gamma-radiation-induced thymic lymphomas.
Carcinogenesis 2006 May
PMID:Epigenetic silencing of E- and N-cadherins in the stroma of mouse thymic lymphomas. 2721 82

Genes that are active during normal development are frequently reactivated during neoplastic transformation. We now report that developmentally expressed TAp63 isoforms are frequently reactivated in human squamous cell carcinomas. To determine the consequences of TAp63 reactivation, we induced TAp63alpha expression during chemically-induced skin carcinogenesis. Deregulated TAp63alpha expression dramatically accelerated tumor development and progression, frequently resulting in epithelial-mesenchymal transitions to spindle cell carcinomas and lung metastases. Consistent with this observation, we detected high levels of Twist and N-cadherin in tumors overexpressing TAp63alpha. Thus, as observed for other developmental pathways, aberrant reactivation of TAp63 predisposes to tumor development and progression.
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PMID:Reactivation of developmentally expressed p63 isoforms predisposes to tumor development and progression. 1661 15

The genetic basis of pancreatic ductal adenocarcinoma, which constitutes the most common type of pancreatic malignancy, involves the sequential activation of oncogenes and inactivation of tumor suppressor genes. Among the pivotal genetic alterations are Ki-RAS oncogene activation and p53 tumor suppressor gene inactivation. We explain that the combination of these genetic events facilitates pancreatic carcinogenesis as revealed in novel three-dimensional cell (spheroid cyst) culture and in vivo subcutaneous and orthotopic xenotransplantation models. N-cadherin, a member of the classic cadherins important in the regulation of cell-cell adhesion, is induced in the presence of Ki-RAS mutation but subsequently downregulated with the acquisition of p53 mutation as revealed by gene microarrays and corroborated by reverse transcription-PCR and Western blotting. N-cadherin modulates the capacity of pancreatic ductal cells to migrate and invade, in part via complex formation with keratinocyte growth factor receptor and neural cell adhesion molecule and in part via interaction with p120-catenin. However, modulation of these complexes by Ki-RAS and p53 leads to enhanced cell migration and invasion. This preferentially induces the downstream effector AKT over mitogen-activated protein kinase to execute changes in cellular behavior. Thus, we are able to define molecules that in part are directly affected by Ki-RAS and p53 during pancreatic ductal carcinogenesis, and this provides a platform for potential new molecularly based therapeutic interventions.
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PMID:N-cadherin and keratinocyte growth factor receptor mediate the functional interplay between Ki-RASG12V and p53V143A in promoting pancreatic cell migration, invasion, and tissue architecture disruption. 1670 70

Id-1 (inhibitor of differentiation or DNA binding-1) has been positively associated with cell proliferation, cell cycle progression, and invasiveness during tumorigenesis. In addition, Id-1 has been shown to modulate cellular sensitivity to TGF-beta1 (transforming growth factor beta1). Here we demonstrate a novel role of Id-1 in promoting TGF-beta1-induced cell motility in a non-malignant prostate epithelial cell line, NPTX. We found that Id-1 promoted F-actin stress fiber formation in response to TGF-beta1, which was associated with increased cell-substrate adhesion and cell migration in NPTX cells. In addition, this positive effect of Id-1 on TGF-beta1-induced cell motility was mediated through activation of MEK-ERK signaling pathway and subsequent phosphorylation of HSP27 (heat shock protein 27). Furthermore, Id-1 disrupted the adherens junction complex in TGF-beta1-treated cells through down-regulation of E-cadherin, redistribution of beta-catenin, along with up-regulation of N-cadherin. These lines of evidence reveal a novel tumorigenic role of Id-1 through reorganization of actin cytoskeleton and disassembly of cell-cell adhesion in response to TGF-beta1 in human prostate epithelial cells, and suggest that intracellular Id-1 levels might be a determining factor for switching TGF-beta1 from a growth inhibitor to a tumor promoter during prostate carcinogenesis.
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PMID:Id-1 promotes TGF-beta1-induced cell motility through HSP27 activation and disassembly of adherens junction in prostate epithelial cells. 1791 52


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