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
Monday, January 30th, 2006.
Journal of Cellular Physiology. 2006 Jan 30; [Epub ahead of print]. [Link]
Zhong J, Cornelsen Gencay MM, Bubendorf L, Burgess JK, Parson H, Robinson BW, Tamm M, Black JL, Roth M.
Department of Pharmacology, The Woolcock Institute of Medical Research, University of Sydney, New South Wales, Australia.
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)-beta(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-beta(1) inhibited cell proliferation. PDGF-BB was a chemoattractant for mesothelial cells, and its effect was increased in the presence of TGF-beta(1). TGF-beta(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.
Glossary
- platelet
- a part of the blood that helps it "stick together" (clot) to promote healing after an injury. Chemotherapy can cause a drop in the platelet count--a condition called thrombocytopenia.
- growth factors
- a naturally occurring protein that causes cells to grow and divide. Too much growth factor production by some cancer cells helps them grow quickly, and new treatments to block these growth factors are being tested in clinical trials. Other growth factors help normal cells recover from side effects of chemotherapy.
- gene
- a segment of DNA that contains information on hereditary characteristics such as hair color, eye color, and height, as well as susceptibility to certain diseases. Women who have BRCA1 or BRCA2 gene mutations (defects) have an inherited tendency to develop breast cancer.
- cell
- the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.
- tissue
- a collection of cells, united to perform a particular function.
- tumor
- an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).
- mesothelioma
- a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.
