title: S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis.
abstract: 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 physiologic and pathophysiologic 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 (MMP) by S100A9 was markedly downregulated in melanoma cells by attenuation of EMMPRIN. We found that EMMPRIN signaling used 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. Immunohistologic analysis of melanomas revealed that EMMPRIN was expressed at both the invasive edge of lesions and 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 use in targeting S100A9-EMMPRIN interactions.
authors.affiliation: Shiseido Innovative Science Research & Development Center, Yokohama, Japan. toshihiko.hibino1@to.shiseido.co.jp
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hibino
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.forename: Shoko
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Mami
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Motoyama
authors.forename: Junichi
authors.initials: J
authors.lastname: Hosoi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Shimokata
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Ito
authors.forename: Ryoji
authors.initials: R
authors.lastname: Tsuboi
authors.forename: Nam-Ho
authors.initials: NH
authors.lastname: Huh
mesh_terms: D000818:Animals; D051926:Basigin / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008024:Ligands; D013058:Mass Spectrometry; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D040502:Calgranulin B; D008024:Ligands; D034741:RNA, Small Interfering; D051926:Basigin