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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antigens, CD*
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Antigens, Neoplasm*
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Basigin
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Biomarkers, Tumor
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Bronchi / enzymology
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Carcinoma, Non-Small-Cell Lung / enzymology*
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Carcinoma, Non-Small-Cell Lung / genetics*
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Cell Line
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Collagenases / genetics*
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Epithelial Cells / enzymology
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Humans
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Kinetics
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Lung / metabolism
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Lung Neoplasms / enzymology*
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Lung Neoplasms / genetics*
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Matrix Metalloproteinase 1
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Membrane Glycoproteins / metabolism*
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Mitogen-Activated Protein Kinases*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Transcription, Genetic*
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p38 Mitogen-Activated Protein Kinases
Substances
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Antigens, CD
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Antigens, Neoplasm
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BSG protein, human
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Biomarkers, Tumor
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Membrane Glycoproteins
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RNA, Messenger
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Basigin
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Collagenases
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Matrix Metalloproteinase 1