Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions

Extracellular matrix metalloproteinase inducer (EMMPRIN: CD147) is a heavil y glycosylated protein containing two immunoglobulin superfamily domains. I t is enriched on the surface of tumor cells and stimulates the production o f matrix metalloproteinases (MMPs) by adjacent stromal cells. Here we use C D147 transfectants and immobilized recombinant CD147-Fc fusion protein to s how that CD147/EMMPRIN engages in a homophilic interaction, predominantly t hrough the first immunoglobulin domain. Anti-CD147 antibody 8G6 and recombi nant CD147-Fc fusion protein markedly inhibited not only homophilic interac tion, but also the production of secreted MMP-2 by breast cancer cell line MDA-435 and the MMP-2-dependent invasion of MDA-435 cells through reconstit uted basement-membrane Matrigel. Purified native CD147 induced the producti on of secreted MMP not only by dermal fibroblasts (MMP-1) but also by MDA-4 35 cells themselves (MMP-2), suggesting homophilic CD147-binding may occur in the context of both heterotypic and homotypic cell-cell interactions. Pu rified deglycosylated CD147 failed to induce MMP-1 or MMP-2, but instead an tagonized the MMP-1-inducing activity of purified native CD147, Our results suggest that homophilic CD147 interactions may play a key role in MMP-2 pr oduction and tumor cell invasion, and that perturbation of this molecule ma y have potential therapeutic uses in the prevention of MMP-2 and MMP-1-depe ndent cancer metastasis.