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Overexpression of E-cadherin on melanoma cells inhibits chemokine-promoted invasion involving p190RhoGAP/p120ctn-dependent inactivation of RhoA.

ABSTRACT: 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.

SUBMITTER: Molina-Ortiz I

PROVIDER: S-EPMC2685696 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Overexpression of E-cadherin on melanoma cells inhibits chemokine-promoted invasion involving p190RhoGAP/p120ctn-dependent inactivation of RhoA.

Molina-Ortiz Isabel I Bartolomé Rubén A RA Hernández-Varas Pablo P Colo Georgina P GP Teixidó Joaquin J

The Journal of biological chemistry 20090317 22

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 ...[more]

PMID: 19293150

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Project description:Background: Nasopharyngeal carcinoma (NPC) is a kind of head and neck squamous cell carcinoma (HNSCC) with a strong tendency for metastasis and recurrence. Non-muscle myosin heavy chain IIA (NMHC IIA) plays important roles in recurrence and metastasis of cancers. However, the function and mechanism of NMHC IIA expression in NPC remain unclear. Methods: A receiver operating characteristic (ROC) curve was constructed for 141 specimens of HNSCC tissues and 44 control samples from The Cancer Genome Atlas (TCGA) database. Co-expressed genes with MYH9 were identified using LinkedOmics. Transcription factors (TFs) and miRNA regulation network were constructed using Networkanalyst. The migration and invasion ability of nasopharyngeal carcinoma cells were evaluated by in vitro migration and matrigel invasion assays, respectively. Results: The public microarray results showed that MYH9 expression levels were upregulated in HNSCC tissues compared with the matched adjacent normal tissues in this study (p<0.0001). The AUC of MYH9 reached up to 0.8303 at a cutoff value of 175.2, with a sensitivity and specificity of 70.21% and 86.36%, respectively. MYH9 expression was increased in lymph node metastasis HNSCC tumors compared with that in tumors without lymph node metastasis (p<0.05) and showed a strong positive association with expression of FLNA. High MYH9 and FLNA expression were related with poorer overall survival in HNSCC. MYH9 with positively associated genes regulated focal adhesion, cell-substrate junction assembly and cell morphogenesis were involved in differentiation using GO and KEGG analysis. MYH9 was correlated with a network of TFs including SP1, SRF, JUN and FOS in HNSCC. The suppression of endogenous NMHC IIA decreased cellular migration and invasion in HNE1 cells and reduced the expression of phosphorylation of EGFR, AKT and ERK. The over-expression of NMHC IIA increased cellular migration and invasion in COS-7 cells and increased the expression of phosphorylation of EGFR, AKT and ERK. Conclusion: Expression of NMHC IIA mRNA was higher in HNSCC than in the adjacent normal tissues. NMHC IIA expression was increased in lymph node metastasis HNSCC tumors compared with tumors without lymph node metastasis. High MYH9 was association with poorer overall survival in HNSCC. NMHC IIA expression increased the invasion and metastasis abilities of the nasopharyngeal cancer cell line in vitro by augmenting the expression of phosphorylation of EGFR, AKT and ERK. These findings will be beneficial for providing an effectively therapeutic strategy for NPC.

Dataset Information

Overexpression of E-cadherin on melanoma cells inhibits chemokine-promoted invasion involving p190RhoGAP/p120ctn-dependent inactivation of RhoA.

Publications

Overexpression of E-cadherin on melanoma cells inhibits chemokine-promoted invasion involving p190RhoGAP/p120ctn-dependent inactivation of RhoA.

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