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β-1,3-Galactosyl-O-Glycosyl-Glycoprotein β-1,6-N-Acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility

I Wayan Sumardika*†, Chen Youyi*, Eisaku Kondo, Yusuke Inoue§, I Made Winarsa Ruma*†, Hitoshi Murata*, Rie Kinoshita*, Ken-Ichi Yamamoto*, Shuta Tomida, Kazuhiko Shien#, Hiroki Sato#, Akira Yamauchi**, Junichiro Futami††, Endy Widya Putranto‡‡, Toshihiko Hibino§§, Shinichi Toyooka¶#¶¶, Masahiro Nishibori##, Masakiyo Sakaguchi*

* Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
† Faculty of Medicine, Udayana University, Bali, Indonesia
‡ Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
§ Faculty of Science and Technology, Division of Molecular Science, Gunma University, Gunma, Japan
¶ Department of Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
# Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
** Department of Biochemistry, Kawasaki Medical School, Okayama, Japan
†† Department of Medical and Bioengineering Science, Okayama University Graduate School of Natural Science and Technology, Okayama, Japan
‡‡ Department of Pediatrics, Dr. Sardjito Hospital/Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
§§ Department of Dermatology, Tokyo Medical University, Tokyo, Japan
¶¶ Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
## Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Oncology Research 2018, 26(3), 431-444. https://doi.org/10.3727/096504017X15031557924123

Abstract

We previously identified novel S100A8/A9 receptors, extracellular matrix metalloproteinase inducer (EMMPRIN), melanoma cell adhesion molecule (MCAM), activated leukocyte cell adhesion molecule (ALCAM), and neuroplastin (NPTN) β, that are critically involved in S100A8/A9-mediated cancer metastasis and inflammation when expressed at high levels. However, little is known about the presence of any cancerspecific mechanism(s) that modifies these receptors, further inducing upregulation at protein levels without any transcriptional regulation. Expression levels of glycosyltransferase-encoding genes were examined by a PCRbased profiling array followed by confirmation with quantitative real-time PCR. Cell migration and invasion were assessed using a Boyden chamber. Western blotting was used to examine the protein level, and the RNA level was examined by Northern blotting. Immunohistochemistry was used to examine the expression pattern of β-1,3-galactosyl-O-glycosyl-glycoprotein β-1,6-N-acetylglucosaminyltransferase 3 (GCNT3) and MCAM in melanoma tissue. We found that GCNT3 is overexpressed in highly metastatic melanomas. Silencing and functional inhibition of GCNT3 greatly suppressed migration and invasion of melanoma cells, resulting in the loss of S100A8/A9 responsiveness. Among the novel S100A8/A9 receptors, GCNT3 favorably glycosylates the MCAM receptor, extending its half-life and leading to further elevation of S100A8/A9-mediated cellular motility in melanoma cells. GCNT3 expression is positively correlated to MCAM expression in patients with high-grade melanomas. Collectively, our results showed that GCNT3 is an upstream regulator of MCAM protein and indicate the possibility of a potential molecular target in melanoma therapeutics through abrogation of the S100A8/A9–MCAM axis.

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APA Style
Sumardika, I.W., Youyi, C., Kondo, E., Inoue, Y., Ruma, I.M.W. et al. (2018). β-1,3-galactosyl-o-glycosyl-glycoprotein β-1,6-n-acetylglucosaminyltransferase 3 increases MCAM stability, which enhances s100a8/a9-mediated cancer motility. Oncology Research, 26(3), 431-444. https://doi.org/10.3727/096504017X15031557924123
Vancouver Style
Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, et al. β-1,3-galactosyl-o-glycosyl-glycoprotein β-1,6-n-acetylglucosaminyltransferase 3 increases MCAM stability, which enhances s100a8/a9-mediated cancer motility. Oncol Res. 2018;26(3):431-444 https://doi.org/10.3727/096504017X15031557924123
IEEE Style
I.W. Sumardika et al., "β-1,3-Galactosyl-O-Glycosyl-Glycoprotein β-1,6-N-Acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility," Oncol. Res., vol. 26, no. 3, pp. 431-444. 2018. https://doi.org/10.3727/096504017X15031557924123



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