DOWN-REGULATION OF E-CADHERIN IN MOUSE SKIN CARCINOMA-CELLS ENHANCES A MIGRATORY AND INVASIVE PHENOTYPE LINKED TO MATRIX METALLOPROTEINASE-9 GELATINASE EXPRESSION

yTo assess the role of gelatinases in mouse skin tumor progression and their link to the expression of E-cadherin (E-CD), the cell-cell adhe sion protein, we used the highly metastatic squamous HaCa4 cell line a nd several HaCa4-derived clones obtained by transfection of the mouse E-CD cDNA. Expression of matrix metalloproteinase-9 (MMP-9) mRNA and p rotein activity were present in E-CD (-) HaCa4 and control clones in c ulture, but they were strongly diminished in E-CD (+) clones (E24 and E62) at subconfluence. To explore the suppressive effect of the cell-c ell contacts mediated by E-CD on MMP-9 expression, we introduced a pla smid encoding mouse E-CD antisense cDNA into the E24 cell clone. The t ransfectant P1-clones obtained with reduced or absent E-CD expression showed increased levels of MMP-9 gelatinase, motility in vitro, and me tastatic potential in vivo. Expression of MMP-9 in the various cell cl ones was also negatively modulated by cell density, but this effect wa s much stronger in E-CD (+) cells, despite the fact that all of the ce ll clones analyzed maintained the expression of P-cadherin and made ce ll-cell contacts at high cell density. Our results indicate that in th is cell system, the E-CD-mediated cell-cell contacts are involved in t he down-regulation of MMP-9 expression. Thus, the loss of E-CD trigger s a migratory and invasive phenotype in mouse squamous carcinoma cells .