title: MCAM, as a novel receptor for S100A8/A9, mediates progression of malignant melanoma through prominent activation of NF-κB and ROS formation upon ligand binding.
abstract: The dynamic interaction between tumor cells and their microenvironment induces a proinflammatory milieu that drives cancer development and progression. The S100A8/A9 complex has been implicated in chronic inflammation, tumor development, and progression. The cancer microenvironment contributes to the up-regulation of this protein complex in many invasive tumors, which is associated with the formation of pre-metastatic niches and poor prognosis. Changing adhesive preference of cancer cells is at the core of the metastatic process that governs the reciprocal interactions of cancer cells with the extracellular matrices and neighboring stromal cells. Cell adhesion molecules (CAMs) have been confirmed to have high-level expression in various highly invasive tumors. The expression and function of CAMs are profoundly influenced by the extracellular milieu. S100A8/A9 mediates its effects by binding to cell surface receptors, such as heparan sulfate, TLR4 and RAGE on immune and tumor cells. RAGE has recently been identified as an adhesion molecule and has considerably high identity and similarity to ALCAM and MCAM, which are frequently over-expressed on metastatic malignant melanoma cells. In this study, we demonstrated that ALCAM and MCAM also function as S100A8/A9 receptors as does RAGE and induce malignant melanoma progression by NF-κB activation and ROS formation. Notably, MCAM not only activated NF-κB more prominently than ALCAM and RAGE did but also mediated intracellular signaling for the formation of lung metastasis. MCAM is known to be involved in malignant melanoma development and progression through several mechanisms. Therefore, MCAM is a potential effective target in malignant melanoma treatment.
authors.affiliation: Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.|Faculty of Medicine, Udayana University, Denpasar, 80232, Indonesia.
authors.forename: I Made Winarsa
authors.initials: IM
authors.lastname: Ruma
authors.affiliation: Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.|Faculty of Medicine, Gajah Mada University, Yogyakarta, 55281, Indonesia.
authors.forename: Endy Widya
authors.initials: EW
authors.lastname: Putranto
authors.affiliation: Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medicine and Dental Sciences, 757, Ichiban-cho, Asahimachidori, Chuo-ku, Niigata-shi, Niigata, 951-8510, Japan.
authors.forename: Eisaku
authors.initials: E
authors.lastname: Kondo
authors.affiliation: Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Murata
authors.affiliation: Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Kinoshita
authors.affiliation: Department of Medical and Bioengineering Science, Okayama University Graduate School of Natural Science and Technology, 3-1-1, Tsushima-Naka, Kita-ku, Okayama, 700-8530, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Futami
authors.affiliation: Faculty of Science and Technology, Division of Molecular Science, Gunma University, 1-5-1 Tenjin-cho, Kiryu-shi, Maebashi, 376-8515, Gunma, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Biochemistry, Kawasaki Medical School, 577 Matsushima, Kurashiki-shi, Okayama, 701-0192, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yamauchi
authors.affiliation: Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.|Faculty of Medicine, Udayana University, Denpasar, 80232, Indonesia.
authors.forename: I Wayan
authors.initials: IW
authors.lastname: Sumardika
authors.affiliation: Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
authors.forename: Chen
authors.initials: C
authors.lastname: Youyi
authors.affiliation: Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Nasu
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
authors.affiliation: Department of Dermatology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hibino
authors.affiliation: Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan. masa-s@md.okayama-u.ac.jp.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D051929:CD146 Antigen / Q000235:genetics / Q000378:metabolism; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D015703:Antigens, CD; D051929:CD146 Antigen; D040501:Calgranulin A; D040502:Calgranulin B; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; C000593871:AGER protein, human; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C497902:MCAM protein, human
keywords: ALCAM; MCAM; Malignant melanoma; NF-κB; RAGE; S100A8/A9