Elucidation of the expression mechanism of the glycosyltransferase alpha4GnT that biosynthesizes the gastric adenocarcinoma suppressor alphaGlcNAc

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K17779
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology; Pathological medical chemistry
• Research Institution: Shinshu University
• Principal Investigator: Komura Hitomi 信州大学, 医学部, 特任助教 (30616032)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: 胃癌 / 分化型腺癌 / αGlcNAc / α４GnT / A4gnt欠損マウス / マウス胎児

Outline of Final Research Achievements

Previously, we identified human α1, 4-N-acetylglucosaminyltransferase (α4GnT) that biosynthesizes O-glycans carrying terminal α1, 4-linked N-acetylglucosamine residues (αGlcNAc) in gastric mucosa,　and engineered A4gnt -/- mice. A4gnt -/- mice showed complete lack of αGlcNAc expression in gastric gland mucin. Surprisingly, all the mutant mice developed gastric differentiated-type adenocarcinoma. This result suggests that αGlcNAc serves as a tumor suppressor for differentiated-type adenocarcinoma, but its detailed mechanism is unknown. 3-week-old A4gnt -/- mice develop gastric hyperplasia, so we considered that it is necessary to analyze the embryonic stomach in order to elucidate the carcinogenic mechanism. Therefore, we clarified the expression and localization of α4GnT and related molecules in the embryonic stomach of wild-type mice, and compared the results with that of A4gnt -/-　mice to investigate the causal relationship with carcinogenesis.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

胃癌は分化型腺癌と未分化型腺癌に大別され、分化型腺癌は年齢とともにその罹患率が増加する。全てのA4gnt欠損マウスは、胃の幽門部に分化型腺癌が自然発症することから、分化型腺癌の有用なモデル動物であると考えられる。本研究は、野生型マウス胎児期のα4GnTおよびその関連分子の発現および局在を明らかにし、A4gnt欠損マウスにおけるその変化の様子を観察し、胃の分化型腺癌発症との因果関係を明らかにする。その結果は、腺癌に特化した胃癌発症メカニズムを理解し、胃癌に対する新しい予防法および治療法の確立に大きな道筋を開くものである。