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Cancer Lett. 2019 Jun 28;452:178-190. doi: 10.1016/j.canlet.2019.03.023. Epub 2019 Mar 21.

Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion.

Author information

1
Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan; Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
2
Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan; Faculty of Medicine, Udayana University, Denpasar, 80232, Bali, Indonesia.
3
Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
4
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.
5
Faculty of Science and Technology, Division of Molecular Science, Gunma University, 1-5-1 Tenjin-cho, Kiryu-shi, Gunma, 376-8515, Japan.
6
Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
7
Department of Biochemistry, Kawasaki Medical School, 577 Matsushima, Kurashiki-shi, Okayama, 701-0192, Japan.
8
Department of Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
9
Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
10
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.
11
Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan.
12
Department of Pediatrics, Dr. Sardjito Hospital/Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia.
13
Department of Dermatology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
14
Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
15
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.
16
Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan. Electronic address: masa-s@md.okayama-u.ac.jp.

Abstract

Since metastasis accounts for the majority of cancer-associated deaths, studies on the mechanisms of metastasis are needed to establish innovative strategies for cancer treatment. We previously reported that melanoma cell adhesion molecule (MCAM) functions as a critical receptor for S100A8/A9, and binding of S100A8/A9 to MCAM results in the migration of melanoma cells to lung tissue. However, the critical role of MCAM in the original melanoma skin lesion is still not clear. In this study, we aimed to determine the importance of the S100A8/A9-MCAM axis in melanoma dissemination in a skin lesion as a critical early step for metastasis. Mechanistic studies revealed the downstream signaling of MCAM that signaled the induction of metastasis. S100A8/A9-MCAM binding activates mitogen-activated protein kinase kinase kinase 8 (MAP3K8), also termed TPL2, leading to strong activation of the transcription factor ETV4 and subsequent induction of matrix metalloproteinase-25 (MMP25), and finally to induction of melanoma lung tropic metastasis. Collectively, our results demonstrate a crucial role of the S100A8/A9-MCAM signaling axis in metastatic onset of melanoma cells and indicate that strategies targeting the identified pathway may be useful for the establishment of innovative anti-cancer therapies.

KEYWORDS:

Inflammation; Matrix metalloproteinase; Metastasis; S100 protein; Seed and soil hypothesis

PMID:
30904617
DOI:
10.1016/j.canlet.2019.03.023
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