Transforming growth factor-b1 modulates matrix metalloproteinase-9 production through the Ras/MAPK signaling pathway in transformed keratinocytes

Abstract

Mouse transformed keratinocytes cultured in the presence of transforming growth factor-b1 (TGF-b1) acquire a set ofmorphological and functional properties giving rise to a more motile phenotype that expresses mesenchymal markers. In this work, we present evidence showing that TGF-b1 stimulates cellular production ofMMP-9 (Gelatinase B), a metalloproteinase that plays an important role in tumoral invasion. Our results demonstrate that TGF-b1stimulates MMP-9 production and MMP-9 promoter activity in a process that depends ofthe activation ofthe Ras–ERK1,2 MAP kinase pathway. The latter was demonstrated by cellular transfection of TGF-b1-sensitive cells with a RasN17 mutant gene, using PD 098059, a MEK 1,2 inhibitor, and treating cells with anti-sense oligodeoxinucleotides. The enhanced MMP-9 production proved to be an important factor in the acquisition of migratory and invasive properties as shown by the use ofa specific inhibitor of MMP-9 (GM6001) that inhibits the TGF-b1- stimulated invasive and migratory properties ofthese transformed keratinocytes. 2002 Elsevier Science (USA). All rights reserved.