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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

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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.

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Abbreviations

MCAM:

Melanoma cell adhesion molecule

ALCAM:

Activated leukocyte cell adhesion molecule

RAGE,:

Receptor for advanced glycation end products

NF-κB:

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

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Acknowledgments

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).

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Authors and Affiliations

  1. 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

    I. Made Winarsa Ruma, Endy Widya Putranto, Hitoshi Murata, Rie Kinoshita, I. Wayan Sumardika, Chen Youyi, Ken-Ichi Yamamoto & Masakiyo Sakaguchi

  2. 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

    Eisaku Kondo

  3. Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan

    Masami Watanabe, Peng Huang & Yasutomo Nasu

  4. 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

    Junichiro Futami

  5. Faculty of Science and Technology, Division of Molecular Science, Gunma University, 1-5-1 Tenjin-cho, Kiryu-shi, Maebashi, 376-8515, Gunma, Japan

    Yusuke Inoue

  6. Department of Biochemistry, Kawasaki Medical School, 577 Matsushima, Kurashiki-shi, Okayama, 701-0192, Japan

    Akira Yamauchi

  7. 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

    Masahiro Nishibori

  8. Department of Dermatology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan

    Toshihiko Hibino

  9. Faculty of Medicine, Udayana University, Denpasar, 80232, Indonesia

    I. Made Winarsa Ruma & I. Wayan Sumardika

  10. Faculty of Medicine, Gajah Mada University, Yogyakarta, 55281, Indonesia

    Endy Widya Putranto

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  1. I. Made Winarsa Ruma
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Correspondence to Masakiyo Sakaguchi.

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Ruma, I.M.W., Putranto, E.W., Kondo, E. et al. 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. Clin Exp Metastasis 33, 609–627 (2016). https://doi.org/10.1007/s10585-016-9801-2

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