RÉSUMÉ
The plasminogen activator/plasmin system is one of the main protease systems involved in tumor cell invasion and metastasis. Our previous study has shown that plasmin degrades E-cadherin and promotes cell dissemination by downregulation of E-cadherin-mediated cell-cell adhesion in oral squamous cell carcinoma (SCC) cells. To examine the effect of downregulation of the plasminogen activator/plasmin system by alpha2-antiplasmin (alpha2-AP) on cell-cell adhesion mediated by E-cadherin in oral SCC cells, the oral SCC cell line SCCKN was stably transfected with alpha2-AP cDNA. Induction of alpha2-AP expression led to the inhibition of the proteolysis of E-cadherin by plasminogen activator/plasmin in SCC cells, resulting in the enhancement of the cell aggregation and the suppression of the cell motility. Moreover, alpha2-AP also reduced the ability of SCC cells to invade type I collagen gel, and suppressed tumorigenicity in vivo. These results suggested that downregulation of the plasminogen activator/ plasmin system by alpha2-AP might be a potent therapeutic approach to prevent the progression of oral SCC.
Sujet(s)
Cadhérines/métabolisme , Carcinome épidermoïde/métabolisme , Carcinome épidermoïde/anatomopathologie , Fibrinolysine/métabolisme , Régulation de l'expression des gènes tumoraux , Tumeurs de la bouche/métabolisme , Activateurs du plasminogène/métabolisme , Régulation positive , alpha-2-Antiplasmine/métabolisme , Animaux , Adhérence cellulaire , Collagène/métabolisme , Évolution de la maladie , Humains , Mâle , Souris , Souris de lignée BALB C , Souris nudeRÉSUMÉ
The participation of plasminogen activator/plasmin system in the expression and function of E-cadherin was examined in oral squamous cell carcinoma (SCC) cells. Treatment of SCC cells with plasminogen reduced the Ca2+-dependent cell aggregation. SCC cells expressed E-cadherin at the cell membrane, and released a small amount of soluble E-cadherin at 80 kDa in the culture medium. Addition of plasminogen to SCC cells led to a decrease in the amount of E-cadherin of the cell membrane and the enhancement of the shedding of E-cadherin ectodomain. Plasmin directly cleaved E-cadherin of SCC cells and enhanced the motility of SCC cells. These results suggested that plasminogen activator/plasmin system might directly mediate the proteolytic processing of E-cadherin in oral SCC cells and that might facilitate the progression of oral SCC by downregulation of E-cadherin-mediated cell-cell adhesion.
Sujet(s)
Cadhérines/métabolisme , Fibrinolysine/physiologie , Activateurs du plasminogène/physiologie , Technique de Western , Calcium/pharmacologie , Carcinome épidermoïde/métabolisme , Carcinome épidermoïde/anatomopathologie , Carcinome épidermoïde/physiopathologie , Adhérence cellulaire/effets des médicaments et des substances chimiques , Adhérence cellulaire/physiologie , Lignée cellulaire tumorale , Mouvement cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Fibrinolysine/métabolisme , Fibrinolysine/pharmacologie , Humains , Tumeurs de la bouche/métabolisme , Tumeurs de la bouche/anatomopathologie , Tumeurs de la bouche/physiopathologie , Plasminogène/pharmacologie , Facteurs tempsRÉSUMÉ
The immunohistochemical localization of thrombospondin-1 (TSP-1) in human normal oral mucosa and oral squamous cell carcinoma (SCC) was examined. The immunostaining of TSP-1 was mainly localized in the connective tissues adjacent to the epithelium of oral mucosa, whereas epithelial cells showed negligible immunoreactivity for TSP-1. TSP-1 expression was striking in the stroma of SCC. TSP-1 synthesis by SCC cells and fibroblasts in culture was examined by immunoprecipitation with anti-TSP-1 antibody. Fibroblasts produced a large amount of TSP-1, whereas SCC cells secreted little amount of TSP-1. Treatment of fibroblasts by the conditioned medium of SCC cells led to an increase in TSP-1 synthesis. TSP-1 induced haptotactic migration and stimulated the production of matrix metalloproteinase-9 (MMP-9) in SCC cells. These results suggest that TSP-1 in the stroma of oral SCC might be synthesized by mesenchymal cells but not by epithelial cells, and that the synthesis of TSP-1 might be regulated by interaction with SCC cells. TSP-1 accumulated in the stroma might promote the progression of oral SCC by enhancing the motility and proteolytic activity in a paracrine manner.