Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the cloning and characterization of a cancer-associated cell membrane glycoprotein recognized by mAb NCC-3G10. The antibody showed strong reactivity to a wide variety of cancer cells, but only to a limited number of normal cells including lymphocytes, endothelial cells, and basal cells of stratified squamous epithelium. The cDNA for the antigen encodes 178 aa, which includes a putative signal sequence, a potential O-glycosylated extracellular domain, a single transmembrane domain, and a short cytoplasmic tail. Transfection of the cDNA into PLC/PRF/5 liver cancer cells resulted in reduced cell-cell adhesiveness, based on both morphology and results of Ca(2+)-dependent cell aggregation assay. In transfected cells, E-cadherin was markedly decreased at the protein level in inverse proportion to the expression level of the antigen recognized by NCC-3G10, but not at the mRNA level. Aggregation of the antigen by NCC-3G10-coated beads triggered accumulation of actin, suggesting some interplay between this antigen and E-cadherin through actin. When metastatic ability was examined in severe combined immunodeficient mice by injecting PLC/PRF/5 cells into the spleen, the transfectants formed a markedly higher number of metastatic nodules in comparison with controls. We have named this cell membrane glycoprotein, which down-regulates E-cadherin and promotes metastasis, dysadherin.
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PMID:Dysadherin, a cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes metastasis. 1175 60

Decreased E-cadherin expression permits dissociation and widespread dissemination of gastric adenocarcinoma cells. We studied the relationship between paranuclear E-cadherin distribution and the histopathologic characteristics of gastric adenocarcinomas. E-cadherin immunostains of 173 gastric adenocarcinoma sections revealed paranuclear; punctate to vesicular staining in 18% (16/87) of the intestinal-type adenocarcinomas, 30% (17/56) of the diffuse-type adenocarcinomas, and 30% (9/30) of the mired adenocarcinomas. These data suggest that in some gastric adenocarcinomas, there is a defect in transport of E-cadherin to the cell surface, which may prevent intercellular adhesion and encourage dissemination. Of 34 cancers with paranuclear E-cadherin staining, 20 (59%) had paranuclear staining within the nonneoplastic epithelium, but only 22.0% of 100 carcinomas with absent or membranous E-cadherin staining were accompanied by morphologically benign epithelium with paranuclear E-cadherin. In surface epithelium, paranuclear E-cadherin staining colocalized with Griffonia simplicifolia lectin II in the Golgi apparatus. The presence of paranuclear E-cadherin in cancer-associated benign epithelium suggests that the alteration in the E-cadherin molecule responsible for the paranuclear distribution may be an early change in gastric adenocarcinoma progression.
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PMID:Paranuaclear E-cadherin in gastric adenocarcinoma. 1247 82

Cell-cell adhesion determines the polarity of cells and participates in the maintenance of the cell societies called tissues. Cell-cell adhesiveness is generally reduced in human cancers. Reduced intercellular adhesiveness allows cancer cells to disobey the social order, resulting in destruction of histological structure, which is the morphological hallmark of malignant tumors. Reduced intercellular adhesiveness is also indispensable for cancer invasion and metastasis. A tumor-suppressor gene product, E-cadherin, and its undercoat proteins, catenins, which connect cadherins to actin filaments, are located at lateral borders, concentrating on adherens junctions, of epithelial cells and establish firm cell-cell adhesion. The E-cadherin cell adhesion system in cancer cells is inactivated by various mechanisms that reflect the morphological and biological characteristics of the tumor. Silencing of the E-cadherin gene by DNA hypermethylation around the promoter region occurs frequently, even in precancerous conditions. In diffuse infiltrating cancers, mutations are found in the genes for E-cadherin and alpha- and beta-catenins. At the invading front of cancers, the E-cadherin cell adhesion system is inactivated by tyrosine phosphorylation of beta-catenin; an oncogene product, c-erbB-2 protein, is found to associate directly with beta-catenin. The E-cadherin cell adhesion system cross-talks with the Wingless/Wnt signaling pathway through beta-catenin, and expression of genes, which participate in cancer morphogenesis, may be regulated in conjunction with the Wingless/Wnt signaling pathway. Dysadherin, a newly identified cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. In conclusion, inactivation of the E-cadherin cell adhesion system by both genetic and epigenetic mechanisms plays a significant role during multistage human carcinogenesis.
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PMID:Cell adhesion system and human cancer morphogenesis. 1284 64

Dysadherin is a cancer-associated cell membrane glycoprotein. Its cDNA encodes 178 amino acids, including a putative signal sequence, a potential O-glycosylated extracellular domain, a single transmembrane domain, and a short cytoplasmic tail. Dysadherin is believed to down-regulate the expression of E-cadherin, the prime mediator of cell-cell adhesion in epithelial cells, by a posttranscriptional mechanism and promote the metastasis of carcinoma cells. To evaluate the association between dysadherin expression and E-cadherin expression in thyroid carcinoma, immunostaining for dysadherin and E-cadherin was performed in 51 papillary, 10 follicular, and 31 undifferentiated carcinomas. Immunoreactivity for dysadherin, localized at cell-cell boundaries, was detected in 39 of the 51 papillary carcinomas and all 31 undifferentiated carcinomas but not in the follicular carcinomas or normal thyroid tissue controls. Dysadherin expression was significantly higher in undifferentiated carcinoma than in papillary carcinoma and follicular carcinoma and showed significant negative correlation with E-cadherin expression. The degree of dysadherin expression was significantly associated with the prognosis, occurrence of secondary undifferentiated carcinomas, size of the primary tumor, and metastasis to the regional lymph nodes and lungs. In conclusion, a process involving increased dysadherin expression may lead to an adverse clinical outcome.
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PMID:Dysadherin: expression and clinical significance in thyroid carcinoma. 1297 Mar 17

Carbonic anhydrase IX (CA IX) is a cancer-associated transmembrane isoform of zinc metalloenzymes that catalyse interconversion between carbon dioxide and bicarbonate. CA IX is strongly induced by tumor hypoxia and has been proposed to participate in acidification of tumor microenvironment and in cell adhesion. To elucidate the cell adhesion-related role of CA IX, we investigated its subcellular localization and relationship to E-cadherin, a key adhesion molecule whose loss or destabilization is linked to tumor invasion. For this purpose, we generated MDCK cells with constitutive expression of human CA IX protein. During the monolayer formation, CA IX was localized to cell-cell contacts and its distribution in lateral membranes overlapped with E-cadherin. Calcium switch-triggered disruption and reconstitution of cell contacts resulted in relocalization of both CA IX and E-cadherin to cytoplasm and back to plasma membrane. A similar phenomenon was observed in hypoxia-treated and reoxygenated cells. Moreover, CA IX-expressing MDCK cells exhibited reduced cell adhesion capacity and lower levels of Triton-insoluble E-cadherin. Finally, CA IX was found to coprecipitate with beta-catenin. We conclude that CA IX has a capacity to modulate E-cadherin-mediated cell adhesion via interaction with beta-catenin, which could be of potential significance in hypoxia-induced tumor progression.
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PMID:Carbonic anhydrase IX reduces E-cadherin-mediated adhesion of MDCK cells via interaction with beta-catenin. 1456 91

Norcantharidin (NCTD), a potential anti-cancer drug, is the demethylated analog of cantharidin isolated from blister beetles. The present study investigated the effect of NCTD on tumor invasion and metastasis. A cytotoxicity assay of NCTD in CT26 colorectal adenocarcinoma cells showed a dose- and time-dependent decrease in cell viability. NCTD (50 microM)-treated CT26 cells not only showed an inhibited cell invasion of 65.6%, but also decreased the activity of matrix metalloproteinase-2 and -9. NCTD decreased the adhesive ability of CT26 cells in a dose-dependent manner. At a concentration of 100 microM, NCTD showed a down-expression of several cadherin-catenin adhesion molecules, including Desmoglein, N-cadherin, and alpha- and beta-catenin, while there were no obvious changes in E-cadherin and gamma-catenin. Intraperitoneal injection of NCTD (2 mg/kg/day) in BALB/c mice reduced both the pulmonary metastatic capacity of CT26 cells and prolonged the survival day of the mice. These results demonstrated that it was effective in blocking both tumor invasion and metastasis.
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PMID:Inhibitory effect of norcantharidin, a derivative compound from blister beetles, on tumor invasion and metastasis in CT26 colorectal adenocarcinoma cells. 1571 Nov 81

Dysadherin is a recently characterized cancer-associated cell membrane glycoprotein that has a crucial role to cell-cell adhesiveness. The aim of this study was to examine dysadherin expression in head and neck squamous cell carcinoma (HNSCC). A total of 108 tissue specimens of patients with HNSCC were examined using immunostaining for dysadherin, E-cadherin, and the specific lymphatic endothelium marker D2-40. We quantified dysadherin and E-cadherin expression, assessed intratumoral (ILD) and peritumoral lymphatic density (PLD), and examined the possible associations of all the above parameters with clinicopathologic features and outcome. Finally, we used double staining with dysadherin and D2-40 to examine the expression pattern of dysadherin simultaneously with the lymphovasculature environment of HNSCC. High dysadherin expression was correlated with higher clinical stage (chi2, P = 0.01), with the presence of lymph node metastasis at the time of diagnosis (chi2, P = 0.02), and with increased ILD (chi2, P = 0.001). We observed an impressive reverse association between increased dysadherin expression and decreased E-cadherin expression (chi2, P < 0.001). Surprisingly, dysadherin-positive cancer cells usually gathered around areas of high intratumoral lymphatic vessel concentration, surrounding and invading small intratumoral lymphatics. Higher clinical stage and increased dysadherin expression were found to be the only significant independent prognostic factors for overall survival (hazard ratio, 3.94; 95% confidence interval, 1.09-14.27 for clinical stage; hazard ratio, 3.92; 95% confidence interval, 1.46-10.51 for dysadherin). The loss of intercellular adhesiveness and increased dysadherin expression seems to be related to lymphangiogenesis in HNSCC, but this should be confirmed by additional studies. Dysadherin expression might be a promising prognostic marker for separation of patients at higher risk.
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PMID:Dysadherin expression in head and neck squamous cell carcinoma: association with lymphangiogenesis and prognostic significance. 1643 92

Dysadherin is a cancer-associated cell membrane glycoprotein, which downregulates E-cadherin and promotes metastasis. We studied the clinicopathological features in 72 cases of epithelioid sarcoma and in six cases of malignant rhabdoid tumor, and also assessed the immunohistochemical expression of dysadherin, E-cadherin and MIB-1 in epithelioid sarcoma and malignant rhabdoid tumor cases. In addition, we compared dysadherin mRNA expression between epithelioid sarcoma and malignant rhabdoid tumor cell lines, using RT-PCR and real-time quantitative RT-PCR analysis. Immunohistochemical dysadherin expression was more frequently observed in proximal-type epithelioid sarcoma (71%) in comparison with distal-type epithelioid sarcoma (36%) (P = 0.037). Furthermore, seven proximal-type epithelioid sarcoma cases mimicking malignant rhabdoid tumor (histologically classified as the large cell type, accompanied by frequent rhabdoid cells and located in deep soft tissue) were all positive for dysadherin (100%), whereas dysadherin expression was not detected at all in any of the true six malignant rhabdoid tumors (0%). Cell lines established from proximal-type epithelioid sarcoma revealed significantly higher levels of dysadherin mRNA expression, compared with the levels seen in malignant rhabdoid tumor cell lines by real-time quantitative RT-PCR (P = 0.0433). Epithelioid sarcoma patients with dysadherin expression survived for a significantly shorter time than those without dysadherin expression (P = 0.001). In multivariate analysis, dysadherin immunopositivity (P = 0.0004) was one of the two independent adverse prognostic factors. We conclude that dysadherin expression in epithelioid sarcoma is a significant poor prognostic factor and that it is a powerful diagnostic marker for distinguishing epithelioid sarcoma, including the proximal-type epithelioid sarcoma, from malignant rhabdoid tumor. In epithelioid sarcoma, especially in proximal-type epithelioid sarcoma, increased cell disadhesion and motility by dysadherin plays an important role to acquire aggressive biological behavior. However, in malignant rhabdoid tumor, cell growth cycle that is regulated by hSNF5/INI1 gene seems to be critical to lethal biological behavior rather than dysadherin.
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PMID:Prognostic significance of dysadherin expression in epithelioid sarcoma and its diagnostic utility in distinguishing epithelioid sarcoma from malignant rhabdoid tumor. 1655 75

Dysadherin, a cancer-associated membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. This study examined the role of dysadherin in breast cancer progression. Expression of dysadherin was found to be highest in breast cancer cell lines and tumors that lacked the estrogen receptor (ER). Knockdown of dysadherin caused increased association of E-cadherin with the actin cytoskeleton in breast cancer cell lines that expressed E-cadherin. However, knockdown of dysadherin could still suppress cell invasiveness in cells that had no functional E-cadherin, suggesting the existence of a novel mechanism of action. Global gene expression analysis identified chemokine (C-C motif) ligand 2 (CCL2) as the transcript most affected by dysadherin knockdown in MDA-MB-231 cells, and dysadherin was shown to regulate CCL2 expression in part through activation of the nuclear factor-kappaB pathway. The ability of dysadherin to promote tumor cell invasion in vitro was dependent on the establishment of a CCL2 autocrine loop, and CCL2 secreted by dysadherin-positive tumor cells also promoted endothelial cell migration in a paracrine fashion. Finally, experimental suppression of CCL2 in MDA-MB-231 cells reduced their ability to metastasize in vivo. This study shows that dysadherin has prometastatic effects that are independent of E-cadherin expression and that CCL2 could play an important role in mediating the prometastatic effect of dysadherin in ER-negative breast cancer.
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PMID:Chemokine (C-C motif) ligand 2 mediates the prometastatic effect of dysadherin in human breast cancer cells. 1684 64

It has become clear that particular microRNAs (miRNAs) function either as tumour suppressors or oncogenes, whose loss or overexpression, respectively, has diagnostic and prognostic significance. In several cases, miRNAs have been shown to affect target genes that are involved in the control of cell proliferation and apoptosis. However, malignant tumours display additional traits beyond the acquisition of enhanced growth potential and decreased cell death. Malignant disease is associated with altered tumour-host interactions leading to sustained angiogenesis and the ability to invade and metastasize. It is possible that miRNAs may act as master regulators of these aspects of tumour biology. Bioinformatic analysis of putative miRNA binding sites has indicated several novel potential gene targets of cancer-associated miRNAs that function in aspects of cell adhesion, neovascularization and tissue invasion. Among others, we speculate that miRNAs may find new roles in the regulation of E-cadherin, integrin alphavbeta3, hypoxia-inducible factor-1alpha, syndecan-1, lysyl oxidase, adamalysin metalloproteinase-17, tissue inhibitors of metalloproteinase-3, c-Met and CXCR-4 that underpin the tissue architectural changes associated with malignancy.
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PMID:MicroRNAs and the hallmarks of cancer. 1702 96


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