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Suriano G, Oliveira MJ, Huntsman D, Mateus AR, Ferreira P, Casares F et al.. E-cadherin germline missense mutations and cell phenotype: evidence for the independence of cell invasion on the motile capabilities of the cells. Hum Mol Genet 12: 3007-3016

University of Porto, Oporto, Porto, Portugal
Human Molecular Genetics (Impact Factor: 6.68). 12/2003; 12(22):3007-16. DOI: 10.1093/hmg/ddg316
Source: PubMed

ABSTRACT In Hereditary Diffuse Gastric Cancer syndrome, E-cadherin germline mutations of the missense type harbour significant functional consequences. In this study, we have characterised the effect of T340A, A617T, A634V and V832M E-cadherin germline missense mutations on cell morphology, motility and proliferation. Wild-type E-cadherin and A617T expressing cells have an epithelial-like morphology, with polarised cells migrating unidirectionally. T340A and A634V expressing cells, fibroblast-like, have a high motile phenotype. We show that this phenotype is dependent on an increased level of active RhoA. V832M expressing cells grow in piled-up structure of round cells, as an effect of the disturbance of the binding between alpha-catenin and beta-catenin. The destabilisation of the adhesion complex is shown to hamper the motile capabilities of these cells. We did not observe any effect of the E-cadherin mutations on cell proliferation. We show the existence of a genotype-phenotype correlation between different E-cadherin mutations and cell behaviour. However, we demonstrate that the ability of cells expressing the different E-cadherin mutations to invade is independent on their motile capabilities, providing evidence that motility is neither necessary nor sufficient for cells to invade. Our data give new insights into the understanding of the mechanisms linking invasion and E-cadherin mutations in diffuse gastric cancer.

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    • "These molecules are known to play a critical role in cytoskeleton organization and cell motility [31]. It has been revealed that increased RhoA activity, which led to higher migration capacity, was induced by HDGC-associated E-cadherin missense mutations in the extracellular domain [32]. In addition, activation of RhoA through an E-cadherin dependent pathway involves the role of EGFR (epidermal growth factor receptor) [33]. "
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    • "Mutations in CDH1 are the genetic cause of up to 48% of the diffusion gastric cancer kindreds [68], while in contrast to other cancer predisposition syndromes, splice-site and missense mutations are common, suggesting that even reduced E-cadherin expression can be deleterious [69]. "
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    • "For these mutations we analysed the binding energy between E-cadherin and β-catenin and found that none of them significantly alters the binding affinity of β-catenin, according to FoldX prediction. This is in accordance with the in vitro results showing that the hereditary mutation V832M efficiently binds β-catenin, and its pathogenicity seems to be dependent on the inability of the E-cadherin/β-catenin complex to bind α-catenin [32], [33]. "
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