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Experimental Biology and Medicine 232:515-522 (2007)
© 2007 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Molecular Mechanism of Tenascin-C Action on Matrix Metalloproteinase-1 Invasive Potential

Karine A. Galoian, Nandor Garamszegi, Susanna P. Garamszegi and Sean P. Scully1

Department of Orthopedics, University of Miami, School of Medicine, Miami, Florida 33136

To whom requests for reprints should be addressed at 1 Department of Orthopedics and Rehabilitation (D-27), University of Miami, PO Box 016960, Miami, FL 33136. E-mail: sscully{at}med.miami.edu

The aim of the current study was to confirm that tenascin-C large splice variant (TNC320) stimulates matrix metalloproteinase-1 (MMP-1) expression and to elucidate molecular mechanisms underlying this activation. The analysis of gene expression in cultured cells grown under different conditions indicated significant increases of MMP-1 mRNA steady-state levels in the cells treated with TNC320 (200%) compared with TNC220 (100%) and bovine serum albumin (BSA), which served as controls. Gel electrophoresis results demonstrated augmented MMP-1 protein in cells cultured with TNC320, whereas slight up-regulation was noticed in cells treated with TNC220 or fibronectin. Reverse transcriptase polymerase chain reaction results demonstrated significantly higher levels of MMP-1 gene expression in TNC320 cultured cells than in all other treatment groups. The result was confirmed by examining the level of MMP-1 promoter transactivation by different extracellular proteins. Data demonstrated 30-fold activation of MMP-1 promoter by TNC320 treatment in comparison with other treatments (TNC220 or fibronectin) and BSA as a control. Both invasion and collagenase activity assays demonstrated a 3-fold difference in the cells treated with TNC320 in comparison with the control. MMP-1 was quantified by enzyme-linked immunosorbent assay as well. Experiments with constitutively active expression kinases indicated that MMP-1 expression induced by TNC320 was associated with mitogen-activated protein kinase (MAPK) cascade activation. Culture with TNC320 resulted in more than 2-fold activation of MMP1-luciferase in the presence of mitogen-activated protein kinase kinase kinase 1 and also 2-fold down-regulation in the presence of mitogen-activated protein kinase kinase 1. We hypothesize that tenascin-C stimulates invasion via up-regulation of MMP-1 expression through activation of MAPK cascade signaling.

Key Words: chondrosarcoma • invasion • tenascin-C • matrix metalloproteinase-1 • metastasis • MAPK






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