Regulation of the gastric cancer development by gastric gland mucin-specific glycan, alphaGlcNAc

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08613
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Shinshu University
• Principal Investigator: Fujii Chifumi 信州大学, 学術研究院医学系, 助教 (10361982)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 分化型胃がん / 細胞増殖 / 浸潤 / αGlcNAc / MUC1 / PODXL

Outline of Final Research Achievements

Gastric gland mucin harbors unique O-glycans carrying terminal α1,4-linked N-acetylglucosamine residues (αGlcNAc). α1,4-N-acethlglucosaminyltransferase (α4GnT) is the sole enzyme for αGlcNAc biosynthesis. We established α4GnT-expressing AGS cells, a differentiated gastric cancer cell line, using Tet-On system (AGS-A), and analyzed the effects on cancer cell phenotypes. We found that in vitro cell proliferation, invasion, and tumorigenicity of αGlcNAc-positive cells were significantly suppressed compared with control cells. To clarify the molecular mechanism of above phenotypes, we identified 2 novel αGlcNAc-binding proteins, MUC1 and podocalyxin-like protein 1, in AGS-A cells. Galectin-3 binding to MUC1-N terminus region and phosphorylation to MUC1-C terminus region were attenuated by αGlcNAc synthesis in AGS-A cells. These results suggest that αGlcNAc regulates cancer cell phenotypes by modulating MUC1 signal transduction.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

αGlcNAcは、がんの悪性化に従いその産生量が低下することが報告されているが、その意義は不明であった。本研究の成果は、がん細胞にαGlcNAcを産生させると悪性度が低下することを示すものである。この際にがん細胞でαGlcNAcが結合する新規タンパク質2種を同定し、MUC１へのαGlcNAcの結合が、がん細胞の悪性化を制御する分子機構についても明らかにした。これらの新たな知見の学術的意義は非常に高いと考えられる。またαGlcNAcの産生量低下が、がん細胞の悪性度を制御していることを機能的に示すことができたため、αGlcNAcが、がんの診断マーカーとしても有用であることを示唆している。