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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-2¹

Turku Centre for Biotechnology, University of Turku and Åbo Akademi University [J. W., S. L., P. J., V-M. K.], MediCity Research Laboratory [J. W.] and Department of Medical Biochemistry [V-M. K.], University of Turku, and Department of Dermatology [V-M. K.] and Otorhinolaryngology-Head and Neck Surgery [R. G.], Turku University Central Hospital, FIN-20520 Turku, Finland, and Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark [T. K.]

Collagenase-1 [matrix metalloproteinase (MMP)-1] is expressed by stromal fibroblasts of various invasive malignant tumors. Here, we have examined the molecular mechanisms of tumor-induced expression of MMP-1 by stromal fibroblasts. Treatment of fibroblasts with conditioned media of tumor cells derived from squamous cell carcinomas (SCCs) of the oral cavity and larynx resulted in activation of fibroblast MMP-1 expression at the transcriptional level. The induction of MMP-1 expression correlates with activation of c-Jun NH₂-terminal kinase (JNK) and p38 mitogen-activated protein kinase and phosphorylation of c-Jun and activating transcription factor-2 (ATF-2) and is dependent on the activity of p38 mitogen-activated protein kinase. Furthermore, using fibroblasts derived from JNK2-/- mice, we show that JNK2 is required for induction of fibroblast collagenase-3 expression in response to conditioned SCC tumor cell medium. Together, these results provide evidence that stress-activated p38 and JNK pathways play a crucial role in paracrine regulation of collagenolytic capacity of stromal fibroblasts in SCCs and suggest JNK2 as a novel target for inhibition of MMP-1 expression and tumor invasion.

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