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ERK1/2 and p38 MAP kinase control MMP‐2, MT1‐MMP, and TIMP action and affect cell migration: A comparison between mesothelioma and mesothelial cells

2006; Wiley; Volume: 207; Issue: 2 Linguagem: Inglês

10.1002/jcp.20605

1097-4652

Jun Zhong, Mikael Gencay, Lukas Bubendorf, Janette K. Burgess, Holly Parson, B. W. Robinson, Michael Tamm, Judith L. Black, Michael Roth,

Peptidase Inhibition and Analysis

Abstract Pleural malignant mesothelioma is a locally aggressive tumor of mesothelial cell origin. In other tumor types high expression of matrix metalloproteinase (MMP)‐2, together with membrane‐type1‐MMP (MT1‐MMP), and low levels of the tissue inhibitor of MMP (TIMP)‐2 have been correlated with aggressive tumor progression and low survival rates. Therefore, we compared the expression and activation of these three factors and their regulation by two mesothelioma associated growth factors, platelet‐derived growth factor (PDGF)‐BB, and transforming growth factor (TGF)‐β 1 in six human mesothelioma and one mesothelial cell line. Polymerase chain reaction (PCR), immnuoblotting, zymography, and small inhibitory RNAs (siRNA) were used to study gene expression, protein activation, and signal transduction. To proof the relevance of our in vitro data immunohistochemistry was performed in tissue sections. PDGF‐BB induced, while TGF‐β 1 inhibited cell proliferation. PDGF‐BB was a chemoattractant for mesothelial cells, and its effect was increased in the presence of TGF‐β 1 . TGF‐β 1 stimulated the de novo synthesis of pro‐MMP‐2 in both cell types. Pro‐MMP‐2 synthesis involved p38 MAP kinase. In cell culture and tissue sections only mesothelial cells expressed MT1‐MMP. Migration of mesothelioma cells was dependent on the presence of MT1‐MMP. Migration, but not proliferation of mesothelioma cells was inhibited by oleoyl‐ N ‐hydroxylamide, TIMP‐2, and siRNA for MT1‐MMP. Our data suggest that in mesothelioma cells the phosphorylation of p38 MAP kinase is deregulated and is involved in pro‐MMP‐2 expression. Mesothelioma progression depends on an interaction with mesothelial cells that provide MT1‐MMP necessary to activate pro‐MMP‐2 to facilitate migration through an extracellular matrix (ECM) layer. J. Cell. Physiol. 207: 540–552, 2006. © 2006 Wiley‐Liss, Inc.