Clinical & Experimental Metastasis

, Volume 33, Issue 6, pp 609–627 | Cite as

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

  • I. Made Winarsa Ruma
  • Endy Widya Putranto
  • Eisaku Kondo
  • Hitoshi Murata
  • Masami Watanabe
  • Peng Huang
  • Rie Kinoshita
  • Junichiro Futami
  • Yusuke Inoue
  • Akira Yamauchi
  • I. Wayan Sumardika
  • Chen Youyi
  • Ken-Ichi Yamamoto
  • Yasutomo Nasu
  • Masahiro Nishibori
  • Toshihiko Hibino
  • Masakiyo Sakaguchi
Research Paper


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.


S100A8/A9 MCAM ALCAM RAGE NF-κB Malignant melanoma 



Melanoma cell adhesion molecule


Activated leukocyte cell adhesion molecule


Receptor for advanced glycation end products


Nuclear factor kappa-light-chain-enhancer of activated B cells



This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grant–in-Aid for Scientific Research (B), No. 26,290,039; Grant–in-Aid for Challenging Exploratory Research, No. 15K14382) (M. Sakaguchi), from the Takeda Science Foundation (M. Sakaguchi), from the Princess Takamatsu Cancer Research Fund (14-24613; M. Sakaguchi), and from the Kobayashi Foundation for Cancer Research (M. Sakaguchi).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10585_2016_9801_MOESM1_ESM.docx (2.8 mb)
Supplementary material 1 (DOCX 2878 kb)
10585_2016_9801_MOESM2_ESM.docx (12 kb)
Supplementary material 2 (DOCX 12 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • I. Made Winarsa Ruma
    • 1
    • 9
  • Endy Widya Putranto
    • 1
    • 10
  • Eisaku Kondo
    • 2
  • Hitoshi Murata
    • 1
  • Masami Watanabe
    • 3
  • Peng Huang
    • 3
  • Rie Kinoshita
    • 1
  • Junichiro Futami
    • 4
  • Yusuke Inoue
    • 5
  • Akira Yamauchi
    • 6
  • I. Wayan Sumardika
    • 1
    • 9
  • Chen Youyi
    • 1
  • Ken-Ichi Yamamoto
    • 1
  • Yasutomo Nasu
    • 3
  • Masahiro Nishibori
    • 7
  • Toshihiko Hibino
    • 8
  • Masakiyo Sakaguchi
    • 1
  1. 1.Department of Cell Biology, Dentistry and Pharmaceutical SciencesOkayama University Graduate School of MedicineOkayamaJapan
  2. 2.Division of Molecular and Cellular PathologyNiigata University Graduate School of Medicine and Dental SciencesNiigataJapan
  3. 3.Center for Innovative Clinical MedicineOkayama University HospitalOkayamaJapan
  4. 4.Department of Medical and Bioengineering ScienceOkayama University Graduate School of Natural Science and TechnologyOkayamaJapan
  5. 5.Faculty of Science and Technology, Division of Molecular ScienceGunma UniversityMaebashiJapan
  6. 6.Department of BiochemistryKawasaki Medical SchoolOkayamaJapan
  7. 7.Department of PharmacologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  8. 8.Department of DermatologyTokyo Medical UniversityTokyoJapan
  9. 9.Faculty of MedicineUdayana UniversityDenpasarIndonesia
  10. 10.Faculty of MedicineGajah Mada UniversityYogyakartaIndonesia

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