Activation of fibroblast collagenase-1 expression by tumor cells of squamous cell carcinomas is mediated by p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase-2

Collagenase-1 [matrix metalloproteinase (MMP)-1] is expressed by stromal fi broblasts of various invasive malignant tumors. Here, we have examined the molecular mechanisms of tumor-induced expression of MMP-1 by stromal fibrob lasts. Treatment of fibroblasts with conditioned media of tumor cells deriv ed from squamous cell carcinomas (SCCs) of the oral cavity and larynx resul ted in activation of fibroblast MMP-1 expression at the transcriptional lev el. The induction of MMP-1 expression correlates with activation of c-Jun N H2-terminal kinase (JNK) and p38 mitogen-activated protein kinase and phosp horylation of c-Jun and activating transcription factor-2(ATF-2) and is dep endent on the activity of p38 mitogen-activated protein kinase. Furthermore , using fibroblasts derived from JNK2-/- mice, we show that JNK2 is require d for induction of fibroblast collagenase-3 expression in response to condi tioned SCC tumor cell medium. Together, these results provide evidence that stress-activated p38 and JNK pathways play a crucial role in paracrine reg ulation of collagenolytic capacity of stromal fibroblasts in SCCs and sugge st JNK2 as a novel target. for inhibition of MMP-1 expression and tumor inv asion.