Urokinase expression and binding activity associated with the transforminggrowth factor beta(1)-induced migratory and invasive phenotype of mouse epidermal keratinocytes

Transforming growth factor beta(1)(TGF-beta(1)) is a stimulator of malignan t progression in mouse skin carcinogenesis. TGF-beta(1) exerts a differenti al effect on cultured nontumorigenic (MCA3D cell line) and transformed (PDV cell line) keratinocytes. Whereas MCA3D cells are growth arrested and comm itted to die in the presence of the factor, it induces a reversible epithel ial-fibroblastic conversion in PDV cells. This conversion is associated in vivo with a squamous-spindle cell carcinoma transition. Here we have invest igated the role of urokinase (uPA) during malignant progression of transfor med epidermal keratinocytes. We show that the levels of uPA expression/secr etion, and the uPA binding activity to the cell surface, correlate with the invasive and malignant potentials of mouse epidermal cell lines. TGF-beta( 1) enhanced uPA production, the number of uPA cell surface binding sites, a nd the expression of the plasminogen activator inhibitor PAI-1, in transfor med PDV cells, but had no major effect on nontumorigenic MCA3 D keratinocyt es. Increased uPA production depended on the presence of the factor in the culture medium and occurred concomitantly to the stimulation of the migrato ry and invasive abilities of PDV cells. Synthetic peptides containing the a mino terminal sequence of the mature mouse uPA inhibited the binding of uPA to the cell surface and decreased TGF-beta(1)-induced cell motility and in vasiveness. These results demonstrate that the uPA system mediates at least part of the migratory and invasive phenotype induced by TGF-beta(1) in tra nsformed keratinocytes, and suggest a role for uPA on the changes that lead to the appearance of spindle carcinomas. J. Cell. Biochem. 74:61-73, 1999. (C) 1999 Wiley-Liss, Inc.