Down-regulation of E-cadherin in mouse skin carcinoma cells enhances a migratory and invasive phenotype linked to matrix metalloproteinase-9 gelatinase expression.
To assess the role of gelatinases in mouse skin tumor progression and their link to the expression of E-cadherin (E-CD), the cell-cell adhesion protein, we used the highly metastatic squamous HaCa4 cell line and several HaCa4-derived clones obtained by transfection of the mouse E-CD cDNA. Expression of matrix metalloproteinase-9 (MMP-9) mRNA and protein activity were present in E-CD (-) HaCa4 and control clones in culture, but they were strongly diminished in E-CD (+) clones (E24 and E62) at subconfluence. To explore the suppressive effect of the cell-cell contacts mediated by E-CD on MMP-9 expression, we introduced a plasmid encoding mouse E-CD antisense cDNA into the E24 cell clone. The transfectant P1-clones obtained with reduced or absent E-CD expression showed increased levels of MMP-9 gelatinase, motility in vitro, and metastatic potential in vivo. Expression of MMP-9 in the various cell clones was also negatively modulated by cell density, but this effect was much stronger in E-CD (+) cells, despite the fact that all of the cell clones analyzed maintained the expression of P-cadherin and made cell-cell contacts at high cell density. Our results indicate that in this cell system, the E-CD-mediated cell-cell contacts are involved in the down-regulation of MMP-9 expression. Thus, the loss of E-CD triggers a migratory and invasive phenotype in mouse squamous carcinoma cells.
Department of Cancer and Metastasis, Institut de Recerca Oncològica, Barcelona, Spain.
A
A
Llorens
I
I
Rodrigo
L
L
López-Barcons
M
M
Gonzalez-Garrigues
E
E
Lozano
A
A
Vinyals
M
M
Quintanilla
A
A
Cano
A
A
Fabra
D000818:Animals; D016375:Antisense Elements (Genetics) / Q000235:genetics / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
D016375:Antisense Elements (Genetics); D015820:Cadherins; D018076:DNA, Complementary; D012333:RNA, Messenger; D017364:Collagenases; D020780:Matrix Metalloproteinase 9