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Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through
1Department of Anatomy, University of California, San Francisco 94143-0452, USA. mslim@itsa.ucsf.edu
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.
Insights
Extracellular matrix metalloproteinase inducer (EMMPRIN) upregulates matrix metalloproteinase-1 (MMP-1) in lung tumors. This process involves p38 MAP kinase activation in stromal fibroblasts, highlighting a novel mechanism in tumor-associated MMP synthesis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Extracellular matrix metalloproteinase inducer (EMMPRIN) is known to stimulate fibroblast metalloproteinases (MMPs).
- MMPs play a crucial role in tumor progression and extracellular matrix remodeling.
- Understanding the regulation of MMPs by tumor-associated molecules is vital for developing targeted therapies.
Purpose of the Study:
- To investigate the role of EMMPRIN in regulating matrix metalloproteinase-1 (MMP-1) expression in lung tumors.
- To elucidate the molecular mechanism by which EMMPRIN induces MMP-1 in stromal fibroblasts.
- To identify the specific signaling pathways involved in EMMPRIN-mediated MMP-1 upregulation.
Main Methods:
- Quantitative analysis of MMP-1 mRNA expression in lung tumor tissues.
- In vitro cell culture experiments to assess EMMPRIN's effect on MMP-1 mRNA levels.
- Genistein sensitivity assays to evaluate the involvement of tyrosine kinase activity.
- Western blot analysis to measure the activity of MAP kinases (ERK1/2, SAPK/JNK, p38).
- Pharmacological inhibition of p38 MAP kinase using SB203580.
Main Results:
- EMMPRIN strongly induces MMP-1 mRNA expression in stromal fibroblasts adjacent to tumor cells.
- EMMPRIN upregulates MMP-1 mRNA in a concentration-dependent manner, peaking at 24 hours.
- The EMMPRIN-induced MMP-1 expression is sensitive to genistein, indicating tyrosine kinase involvement.
- EMMPRIN specifically activates the p38 MAP kinase pathway, not ERK1/2 or SAPK/JNK.
- Inhibition of p38 MAP kinase activity blocks EMMPRIN-mediated MMP-1 upregulation.
Conclusions:
- EMMPRIN plays a significant role in stimulating MMP-1 synthesis in the tumor microenvironment.
- The p38 MAP kinase pathway is a key mediator of EMMPRIN's effect on MMP-1 expression in fibroblasts.
- This study reveals a novel molecular mechanism for how tumor-associated molecules regulate stromal MMP synthesis.