Glycobiology in diseases arising from impaired synthesis of sulfated glycosaminoglycans

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03386
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Kobe Pharmaceutical University
• Principal Investigator: Kitagawa Hiroshi 神戸薬科大学, 薬学部, 教授 (40221915)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: コンドロイチン硫酸 / プロテオグリカン / グリコサミノグリカン / ガンの増殖・転移 / 表皮幹細胞 / 乾癬 / Raine 症候群 / FAM20C

Outline of Final Research Achievements

Chondroitin sulfate (CS) proteoglycans are ubiquitously distributed on cell surfaces and within extra/pericellular matrices, which provide functional microenvironments to regulate diverse cellular processes. These divergent functions of CS proteoglycans are exerted largely through their CS chains with structural heterogeneity, which are created by collaborative and/or competitive actions of anabolic enzymes for CS biosynthesis. In this study, we found that chondroitin 6-O-sulfotransferase-1 (C6ST-1) knock-out leads to keratinocyte hyperproliferation and impaired skin permeability. In addition, C6ST-1 transgenic mice, which have a higher abundance of 6-O-sulfated chondroitin sulfate, exhibit a higher bone mineral density. Moreover, CS promotes cancer aggressiveness through the ROR1JNK axis in MDA-MB-231 cells. These findings strongly indicate the physiological significance of the specific sulfation in CS chains.

Free Research Field

生化学・分子生物学・糖鎖生物学

Academic Significance and Societal Importance of the Research Achievements

本研究から、コンドロイチン硫酸鎖の合成異常が、表皮幹細胞の増殖や骨代謝に影響を与え、疾患を発症する原因となることや、がん細胞の増殖・浸潤過程でもコンドロイチン硫酸鎖がシグナル分子として機能することが明らかとなった。本研究の成果は、コンドロイチン硫酸鎖の発現や構造をコントロールすることによって、表皮幹細胞の増殖や骨代謝、さらにがん細胞の増殖・浸潤が制御可能であることを示し、学術的にも意義深い。また、従来の作用点とは全く異なる革新的な治療薬の開発が可能になると思われる。