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(American Journal of Pathology. 2003;163:653-661.)
© 2003 American Society for Investigative Pathology

E-Cadherin Mediates MMP Down-Regulation in Highly Invasive Bronchial Tumor Cells

Béatrice Nawrocki-Raby*, Christine Gilles{dagger}, Myriam Polette*, Corinne Martinella-Catusse*, Noël Bonnet*, Edith Puchelle*, Jean-Michel Foidart{dagger}, Frans van Roy{ddagger} and Philippe Birembaut*

From Institut National de la Santé et de la Recherche Mèdicale (INSERM) Unité Mixte de Recherche Santé (UMRS) 514,* Laboratoire Pol Bouin, Reims, France; the Laboratory of Tumor and Developmental Biology,{dagger} University of Liège, Liège, Belgium; and the Department for Molecular Biomedical Research,{ddagger} Vlaams Interuni-versitair Institut Voor Biotechnologie-Ghent University, Ghent, Belgium

The disorganization of E-cadherin/catenin complexes and the overexpression of matrix metalloproteinases (MMPs) are frequently involved in the capacity of epithelial cells to acquire an invasive phenotype. The functional link between E-cadherin and MMPs was studied by transfecting invasive bronchial BZR tumor cells with human E-cadherin cDNA. Using different in vitro (cell dispersion, modified Boyden chamber) and in vivo assays (human airway epithelial xenograft), we showed that E-cadherin-positive clones displayed a decrease of invasive abilities. As shown by immunoprecipitation, the re-expressed E-cadherin was able to sequestrate one part of free cytoplasmic ß-catenin in BZR cells. The decrease of ß-catenin transcriptional activity in E-cadherin-transfected clones was demonstrated using the TOP-FLASH reporter construct. Finally, we observed a decrease of MMP-1, MMP-3, MMP-9, and MT1-MMP, both at the mRNA and at the protein levels, in E-cadherin-positive clones whereas no changes in MMP-2, TIMP-1, or TIMP-2 were observed when compared with control clones. Moreover, zymography analysis revealed a loss of MMP-2 activation ability in E-cadherin-positive clones treated with the concanavalin A lectin. These data demonstrate a direct role of E-cadherin/catenin complex organization in the regulation of MMPs and suggest an implication of this regulation in the expression of an invasive phenotype by bronchial tumor cells.






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Copyright © 2003 by the American Society for Investigative Pathology.