Tumor‐derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38

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Abstract
EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibroblast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al. (1993) Cancer Res. 53, 3154–3158). Here we focus on MMP‐1, showing that in lung tumors, MMP‐1's cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMMPRIN‐expressing tumor cells. In vitro, EMMPRIN upregulates MMP‐1 mRNA expression in a concentration‐dependent manner, with a peak accumulation at 24 h. The response is genistein‐sensitive, suggesting it is dependent on tyrosine kinase activity. Analysis of tyrosine phosphorylation‐dependent MAP kinases ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases was elevated in response to EMMPRIN. That p38 activity was required for EMMPRIN stimulation of MMP‐1 was evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor‐associated molecules upregulate MMP synthesis in stromal fibroblasts.