Dentin matrix protein 1 enhances invasion potential of colon cancer cells by bridging matrix metalloproteinase-9 to integrins and CD44.
The up-regulation of various matrix metalloproteinases (MMP), certain cell receptors such as integrins and CD44, and the SIBLING family of integrin-binding glycophosphoproteins have been reported separately and in various combinations for many types of tumors. The mechanisms by which these different proteins may be interacting and enhancing the ability of a cancer cell to survive and metastasize have become an interesting issue in cancer biology. Dentin matrix protein 1 (DMP1) has been known for a number of years to bind to CD44 and ArgGlyAsp sequence-dependent integrins. This SIBLING was recently shown to be able to specifically bind and activate proMMP-9 and to make MMP-9 much less sensitive to inhibition by tissue inhibitors of metalloproteinases and synthetic inhibitors. In this study, we used a modified Boyden chamber assay to show that DMP1 enhanced the invasiveness of the MMP-9 expressing colon cancer cell line, SW480, through Matrigel in a dose-dependant manner. DMP1 (100 nmol/L) increased invasion 4-fold over controls (86.1 +/- 13.9 versus 22.3 +/- 9.8, P < 0.001). The enhanced invasive potential required the presence of MMP-9 and at least one of the cell surface receptors, CD44, alpha(v)beta(3), or alpha(v)beta(5) integrin. The bridging of MMP-9 to the cell surface receptors was shown by both pull-down and fluorescence activated cell sorting experiments. Because all of these proteins were also shown by immunohistochemistry to be expressed in serial sections of a colon adenocarcinoma, we have hypothesized that the MMP-9/DMP1/cell surface complexes observed to enhance cell invasion in vitro may be aiding metastatic events in vivo.
Karadag
Abdullah
A
Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, NIH, Department of Health and Human Services, Bethesda, MD 20892, USA.
Fedarko
Neal S
NS
Fisher
Larry W
LW
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004338:Drug Combinations; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C513309:DMP1 protein, human; D004338:Drug Combinations; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D039302:Integrin alphaVbeta3; D016023:Integrins; D007797:Laminin; D010750:Phosphoproteins; D011509:Proteoglycans; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; C059485:matrigel; D003094:Collagen; D020780:Matrix Metalloproteinase 9