S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis
Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, en se liant à la glycoprotéine de surface EMMPRIN, la protéine S100A9 favorise le processus métastatique d'un mélanome
The calcium binding proteins S100A8 and S100A9 can dimerize to form calprotectin, the release of which during tissue damage has been implicated in inflammation and metastasis. However, receptor(s) mediating the physiological and pathophysiological effects of this damage-associated 'danger signal' are uncertain. In this study, searching for candidate calprotectin receptors by affinity isolation-mass spectrometry, we identified the cell surface glycoprotein EMMPRIN/BASIGIN (CD147/BSG). EMMPRIN specifically bound to S100A9 but not S100A8. Induction of cytokines and matrix metalloproteases (MMPs) by S100A9 was markedly downregulated in melanoma cells by attenuation of EMMPRIN. We found that EMMPRIN signaled utilized the TNF receptor-associated factor TRAF2 distinct from the known S100 binding signaling pathway mediated by RAGE (AGER). S100A9 strongly promoted migration when EMMPRIN was highly expressed, independent of RAGE, whereas EMMPRIN blockade suppressed migration by S100A9. Immunohistological analysis of melanomas revealed that EMMPRIN was expressed at both the invasive edge of lesions as well as the adjacent epidermis, where S100A9 was also strongly expressed. In epidermal-specific transgenic mice, tail vein-injected melanoma accumulated in skin expressing S100A9 but not S100A8. Together, our results establish EMMPRIN as a receptor for S100A9 and suggest the therapeutic utility in targeting S100A9-EMMPRIN interactions.