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Expression of integrin alphavbeta3 correlates with activation of membrane-type matrix metalloproteinase-1 and matrix metalloproteinase-2 in human melanoma cells in vitro and in vivo



Expression of integrin alphavbeta3 correlates with activation of membrane-type matrix metalloproteinase-1 and matrix metalloproteinase-2 in human melanoma cells in vitro and in vivo



International Journal of Cancer 87(1): 12-19, 1 July



Activation of matrix metalloproteinase-2 (MMP-2) is mediated by binding to the complex of membrane-type matrix metalloproteinase-1 (MT1-MMP) with tissue inhibitor of MMP-2 (TIMP-2) on the cell surface. Binding of MMP-2 to integrin alphavbeta3 has been implicated in presenting activated MMP-2 on the cell surface of invasive cells, but interactions with the MT1-MMP-TIMP-2 system have not been considered. Therefore, we studied the expression and interaction of MT1-MMP, MMP-2 and TIMP-2 in the alphavbeta3-negative melanoma cell line BLM and in its beta3-transfected, alphavbeta3-expressing counterpart BLM-beta3, both on cell lines and in xenografts. Total expression levels of MMP-2, MT1-MMP and TIMP-2 did not differ markedly between the alphavbeta3-negative and alphavbeta3-positive cells. Remarkable differences, however, exist in the presence of active MMP-2 and MT1-MMP. Zymography on cell lysates revealed that active MMP-2 was restricted to alphavbeta3-positive cell line and clearly accumulated in xenografts derived from the BLM-beta3 cells, confirming the relevance of this integrin for MMP-2 function. Western blotting of cell lysates showed that processing of proMT1-MMP to the activated form was enhanced in BLM-beta3. The ratio of active and inactive MT1-MMP was 3-fold higher in the beta3-transfectants. Immunofluorescence double-labeling followed by confocal laser microscopy showed co-localization of MT1-MMP and alphavbeta3 on BLM-beta3 cells. In xenografts from BLM-beta3 cells, active MT1-MMP was markedly increased. Our results demonstrate that expression of alphavbeta3 in cell lines and xenografts was accompanied by an accumulation of active MT1-MMP and MMP-2. Furthermore, MT1-MMP and alphavbeta3 are co-localized on the cell membrane of tumor cells. These findings suggest that activated MT1-MMP co-localized with alphavbeta3 may be involved in activation of alphavbeta3-bound MMP-2.

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