Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteonectin is recognised as a marker of metastasis progression in melanoma and has been implicated in the transition from radial to vertical growth phase. A Tetracycline-inducible system was used to regulate Osteonectin protein levels in melanoma cell lines to examine the morphological, biochemical and invasive changes that accompany its altered expression. Assay of protein and phosphorylation changes showed a downregulation of E-cadherin, upregulation of Osteopontin and a corresponding increase in phosphorylation of Focal Adhesion Kinase on Tyr(397) and Tyr(576) concomitant with Osteonectin induction. Melanoma cells overexpressing Osteonectin displayed increased invasive potential, whereas ablation of Osteonectin gene transcription using siRNA suppressed the invasive potential of these cells and resulted in the upregulation of E-cadherin. The recently described interaction of Osteonectin with Integrin Linked Kinase leading to modulation of its activity suggests a mechanism relevant to the loss of E-cadherin and cell adhesion that occurs during melanoma progression. These results indicate a central role for Osteonectin in the regulation of gene expression changes driving the progression of melanoma toward metastasis.
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PMID:Osteonectin downregulates E-cadherin, induces osteopontin and focal adhesion kinase activity stimulating an invasive melanoma phenotype. 1772 18

Caveolin-1 reportedly acts as a tumor suppressor and promotes events associated with tumor progression, including metastasis. The molecular mechanisms underlying such radical differences in function are not understood. Recently, we showed that caveolin-1 inhibits expression of the inhibitor of apoptosis protein survivin via a transcriptional mechanism involving the beta-catenin-Tcf/Lef pathway. Surprisingly, while caveolin-1 expression decreased survivin mRNA and protein levels in HT29(ATCC) human colon cancer cells, this was not the case in metastatic HT29(US) cells. Survivin down-regulation was paralleled by coimmunoprecipitation and colocalization of caveolin-1 with beta-catenin in HT29(ATCC) but not HT29(US) cells. Unlike HT29(ATCC) cells, HT29(US) cells expressed small amounts of E-cadherin that accumulated in intracellular patches rather than at the cell surface. Re-expression of E-cadherin in HT29(US) cells restored the ability of caveolin-1 to down-regulate beta-catenin-Tcf/Lef-dependent transcription and survivin expression, as seen in HT29(ATCC) cells. In addition, coimmunoprecipitation and colocalization between caveolin-1 and beta-catenin increased upon E-cadherin expression in HT29(US) cells. In human embryonic kidney HEK293T and HT29(US) cells, caveolin-1 and E-cadherin cooperated in suppressing beta-catenin-Tcf/Lef-dependent transcription as well as survivin expression. Finally, mouse melanoma B16-F10 cells, another metastatic cell model with low endogenous caveolin-1 and E-cadherin levels, were characterized. In these cells, caveolin-1-mediated down-regulation of survivin in the presence of E-cadherin coincided with increased apoptosis. Thus, the absence of E-cadherin severely compromises the ability of caveolin-1 to develop activities potentially relevant to its role as a tumor suppressor.
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PMID:E-cadherin is required for caveolin-1-mediated down-regulation of the inhibitor of apoptosis protein survivin via reduced beta-catenin-Tcf/Lef-dependent transcription. 1778 36

Previous reports showed that receptor-type protein-tyrosine phosphatase PTPRK co-localizes with beta-catenin at adherens junctions, and in vitro experiments suggested that beta-catenin could be substrate of PTPRK-mediated phosphatase activity. beta-catenin is a molecule endowed with a dual function being involved both in cell adhesion and in Wnt signaling pathway. Here we provide evidence for the role of PTPRK in negatively regulating the beta-catenin transcriptional activity by modulating its intracellular and membrane distribution. Expression of PTPRK protein in HEK293 cells and in PTPRK-null melanoma cell lines, one of which harbors a mutated oncogenic beta-catenin, impairs nuclear accumulation of wild type and oncogenic forms of beta-catenin, limits cytosolic levels of tyrosine-phosphorylated beta-catenin, and leads to re-localization of E-cadherin/beta-catenin complexes in ordered membrane phase along cell-cell contacts. This re-modulation of beta-catenin cellular distribution results in the inhibition of cyclin D1 and c-myc protein expression, whose genes are targets of beta-catenin. Tumor cells upon re-expression of PTPRK have a reduced proliferative and migration capacity. Moreover we show that PTPRK is also active in negatively regulating the transactivating function of beta-catenin in normal melanocytes as confirmed by experiments with silenced PTPRK by specific siRNA. Our data show that PTPRK influences transactivating activity of beta-catenin in non-tumoral and neoplastic cells by regulating the balance between signaling and adhesive beta-catenin, thus providing biochemical basis for the hypothesis of PTPRK as a tumor suppressor gene.
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PMID:PTPRK negatively regulates transcriptional activity of wild type and mutated oncogenic beta-catenin and affects membrane distribution of beta-catenin/E-cadherin complexes in cancer cells. 1827 11

Uveal melanomas frequently metastasize and cause patient death. Many clinical, histopathologic, molecular, and genetic factors have been linked to metastasis. We hypothesized that understanding the relationships between, and relative prognostic significance of these factors would provide new insights into the pathogenesis of metastasis. To this end, we collected clinical, pathologic, and molecular data for 65 uveal melanomas, including patient age, sex, tumor size, location, cell type, vasculogenic mimicry looping matrix patterns, gene expression profiles, and immunohistochemistry for cytokeratin-18, vascular endothelial cadherin, E-cadherin, beta-catenin, and hypoxia-inducible factor 1alpha. In addition, we used Gene Set Enrichment Analysis to identify statistically significant overlap in genes that were differentially expressed in metastasizing tumors and those expressed in other well-characterized biological systems. Our results show that the class 2 gene expression signature was the most accurate predictor of metastasis (P=0.0001) and that the biomarkers most strongly associated with the class 2 signature included epithelioid cell type, beta-catenin, E-cadherin, and hypoxia-inducible factor 1alpha (P< or =0.001 for each). Thus, the class 2 gene expression signature continues to be the most accurate predictor of uveal melanoma metastasis and can, therefore, serve as a benchmark for evaluating other biomarkers. Importantly, Gene Set Enrichment Analysis showed a significant association between genes expressed in class 2 tumors and those expressed in primitive ectodermal and neural stem cells. Taken together with the constellation of biomarkers associated with the class 2 signature, this suggests the presence of cancer cells with a primitive neural/ectodermal stem cell-like phenotype that may be responsible for metastasis in these highly aggressive tumors.
Melanoma Res 2008 Jun
PMID:Prognostic biomarkers in uveal melanoma: evidence for a stem cell-like phenotype associated with metastasis. 1847 93

The inhibitory effects of (-)-epigallocatechin-3-gallate (EGCG) on the invasion of human malignant melanoma cell line A375 and the possible molecular mechanisms of this effect were investigated. A375 cells were pretreated with 20 microg/mL EGCG for 24, 48 and 72 h respectively and the E-cadherin expression was detected by Western blot analysis. A375 cells were also pretreated with different concentrations of EGCG (1, 5, 10 and 20 microg/mL) for 72 h and the expression of E-cadherin was measured by RT-PCR. The adhesion and invasion of A375 cells were tested by cell-matrigel adhesion assay and matrigel invasion assay respectively. The results showed that EGCG could significantly up-regulate the expression of E-cadherin time-and concentration-dependently (both P<0.05). Statistical analysis showed that A375 cells invasion was inhibited by EGCG and correlated with the up-regulation of E-cadherin expression. It was suggested that EGCG strongly inhibited invasion of A375 cells, and the inhibition mechanism was possibly associated with the up-regulation of E-cadherin expression.
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PMID:Inhibition of invasion and up-regulation of E-cadherin expression in human malignant melanoma cell line A375 by (-)-epigallocatechin-3-gallate. 1856 42

Solid pseudopapillary tumours (SPT) of the pancreas are uncommon, but with widespread and increased imaging, several of these lesions are coming to light incidentally and are subject to needle biopsies. On limited material and especially the solid or clear cell, variants of SPT can morphologically mimic most notably pancreatic neuroendocrine tumours and even metastatic renal cell carcinoma or melanoma. In this context, immunohistochemistry is important and useful in helping to reach the correct diagnosis. Several antibodies have been used in the immunohistochemical evaluation of SPT. As with most tumours, no one marker is specific, but rather a core panel is advocated. Recently, both beta-catenin and E-cadherin have been shown to be of value in SPT. Nuclear and cytoplasmic decoration of tumour cells by beta-catenin is seen in almost 100% of cases. This protein relocalisation away from the cell membrane is underscored by mutations of the beta-catenin gene. Mutations of the CDH1 gene are very uncommon in SPT, but the immunohistochemically detected changes to the protein are consistent and present in 100% of cases. Using an E-cadherin antibody to the extracellular domain of the molecule results in complete membrane loss, while the antibody directed to the cytoplasmic fragment produces distinct nuclear staining of the tumour cells. In addition, there is concordance of staining abnormalities between the two antibodies. When combined with CD10 and progesterone receptor positivity, a diagnosis of SPT can be rendered with confidence even in small biopsy samples.
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PMID:Revision 2: an immunohistochemical approach and evaluation of solid pseudopapillary tumour of the pancreas. 1870 24

Although Smad signalling is known to play a tumour suppressor role, it has been shown to play a prometastatic function also in breast cancer and melanoma metastasis to bone. In contrast, mutation or reduced level of Smad4 in colorectal cancer is directly correlated to poor survival and increased metastasis. However, the functional role of Smad signalling in metastasis of colorectal cancer has not been elucidated. We previously reported that overexpression of Smad7 in colon adenocarcinoma (FET) cells induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis. Here, we have observed that abrogation of Smad signalling by Smad7 induces liver metastasis in a splenic injection model. Polymerase chain reaction with genomic DNA from liver metastases indicates that cells expressing Smad7 migrated to the liver. Increased expression of TGF-beta type II receptor in liver metastases is associated with phosphorylation and nuclear accumulation of Smad2. Immunohistochemical analyses have suggested poorly differentiated spindle cell morphology and higher cell proliferation in Smad7-induced liver metastases. Interestingly, we have observed increased expression and junctional staining of Claudin-1, Claudin-4 and E-cadherin in liver metastases. Therefore, this report demonstrates, for the first time, that blockade of TGF-beta/Smad pathway in colon cancer cells induces metastasis, thus supporting an important role of Smad signalling in inhibiting colon cancer metastasis.
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PMID:Smad7 induces hepatic metastasis in colorectal cancer. 1878 Nov 53

The T-box transcription factors Tbx2 and Tbx3 are overexpressed in many cancers and in melanoma promote proliferation by actively suppressing senescence. Whether they also contribute to tumor progression via other mechanisms is not known. Here, we identify a novel role for these factors, providing evidence that Tbx3, and potentially Tbx2, directly repress the expression of E-cadherin, a keratinocyte-melanoma adhesion molecule whose loss is required for the acquisition of an invasive phenotype. Overexpression of Tbx2 and Tbx3 in melanoma cells down-regulates endogenous E-cadherin expression, whereas depletion of Tbx3, but not Tbx2, increases E-cadherin mRNA and protein levels and decreases melanoma invasiveness in vitro. Consistent with these observations, in melanoma tissue, Tbx3 and E-cadherin expression are inversely correlated. Depletion of Tbx3 also leads to substantial up-regulation of Tbx2. The results suggest that Tbx2 and Tbx3 may play a dual role during the radial to vertical growth phase transition by both inhibiting senescence via repression of p21(CIP1) expression, and enhancing melanoma invasiveness by decreasing E-cadherin levels.
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PMID:Tbx3 represses E-cadherin expression and enhances melanoma invasiveness. 1882 43

TGF-beta induces epithelial-mesenchymal transition, which occurs during tumor cell invasiveness in pathological state, in limited cells. As a first step to understand the role of TGF-beta and the structurally related activin during melanoma metastasis, expression of metastasis-related genes was examined in murine melanoma cells. Treatment with TGF-beta1 or activin A down-regulated E-cadherin in B16 cells in a dose-dependent manner. In epithelial cells, TGF-beta-induced high mobility group A2 (HMGA2) gene product is suggested to down-regulate E-cadherin through up-regulation of zinc-finger transcription factors Slug and Snail, and basic helix-loop-helix transcription factor Twist. Unlike the regulation in epithelial cells, TGF-beta1 treatment rather decreased mRNA expression of HMGA2, indicating a distinct mechanism on TGF-beta/activin-induced down-regulation. Transfection of double-stranded interfering RNA (dsRNAi) for activin receptor-like kinase (ALK) type I receptors revealed that ALK5, a prototype of TGF-beta receptor, mainly transmits TGF-beta signals on the E-cadherin down-regulation at the mRNA level, and that a prototype receptor ALK4 elicited the activin effect. TGF-beta/activin potentiated down-regulation of E-cadherin and HMGA2 also in B16 sublines that are susceptible to metastasis. However, the extent of down-regulation tended to be smaller, and less Smad2, a signal mediator for TGF-beta/activin, was phosphorylated in response to the ligand, resulting from less expression of type I receptors in the B16 sublines. These results suggest that the receptor expression level determines strength of the signals for TGF-beta/activin through phosphorylation of Smad2, which explains pluripotency of the ligand family partly.
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PMID:Regulatory expression of genes related to metastasis by TGF-beta and activin A in B16 murine melanoma cells. 1928 18

Melanoma cells express the chemokine receptor CXCR4 that confers high invasiveness upon binding to its ligand CXCL12. Melanoma cells at initial stages of the disease show reduction or loss of E-cadherin expression, but recovery of its expression is frequently found at advanced phases. We overexpressed E-cadherin in the highly invasive BRO lung metastatic cell melanoma cell line to investigate whether it could influence CXCL12-promoted cell invasion. Overexpression of E-cadherin led to defective invasion of melanoma cells across Matrigel and type I collagen in response to CXCL12. A decrease in individual cell migration directionality toward the chemokine and reduced adhesion accounted for the impaired invasion. A p190RhoGAP-dependent inhibition of RhoA activation was responsible for the impairment in chemokine-stimulated E-cadherin melanoma transfectant invasion. Furthermore, we show that p190RhoGAP and p120ctn associated predominantly on the plasma membrane of cells overexpressing E-cadherin, and that E-cadherin-bound p120ctn contributed to RhoA inactivation by favoring p190RhoGAP-RhoA association. These results suggest that melanoma cells at advanced stages of the disease could have reduced metastatic potency in response to chemotactic stimuli compared with cells lacking E-cadherin, and the results indicate that p190RhoGAP is a central molecule controlling melanoma cell invasion.
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PMID:Overexpression of E-cadherin on melanoma cells inhibits chemokine-promoted invasion involving p190RhoGAP/p120ctn-dependent inactivation of RhoA. 1929 50


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