Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
J Clin Invest. 2012 Mar;122(3):923-34. doi: 10.1172/JCI59087. Epub 2012 Feb 6.
Gastric gland mucin secreted from the lower portion of the gastric mucosa contains unique O-linked oligosaccharides (O-glycans) having terminal α1,4-linked N-acetylglucosamine residues (αGlcNAc). Previously, we identified human α1,4-N-acetylglucosaminyltransferase (α4GnT), which is responsible for the O-glycan biosynthesis and characterized αGlcNAc function in suppressing Helicobacter pylori in vitro. In the present study, we engineered A4gnt(-/-) mice to better understand its role in vivo. A4gnt(-/-) mice showed complete lack of αGlcNAc expression in gastric gland mucin. Surprisingly, all the mutant mice developed gastric adenocarcinoma through a hyperplasia-dysplasia-carcinoma sequence in the absence of H. pylori infection. Microarray and quantitative RT-PCR analysis revealed upregulation of genes encoding inflammatory chemokine ligands, proinflammatory cytokines, and growth factors, such as Ccl2, Il-11, and Hgf in the gastric mucosa of A4gnt(-/-) mice. Further supporting an important role for this O-glycan in cancer progression, we also observed significantly reduced αGlcNAc in human gastric adenocarcinoma and adenoma. Our results demonstrate that the absence of αGlcNAc triggers gastric tumorigenesis through inflammation-associated pathways in vivo. Thus, αGlcNAc-terminated gastric mucin plays dual roles in preventing gastric cancer by inhibiting H. pylori infection and also suppressing tumor-promoting inflammation.
胃黏膜下层分泌的胃腺体黏液含有独特的 O-连接寡糖（O-聚糖），其末端具有α1,4 连接的 N-乙酰葡萄糖胺残基（αGlcNAc）。先前，我们鉴定了人类α1,4-N-乙酰氨基葡萄糖基转移酶（α4GnT），它负责 O-聚糖生物合成，并表征了αGlcNAc 在体外抑制幽门螺杆菌的功能。在本研究中，我们构建了 A4gnt(-/-) 小鼠以更好地了解其在体内的作用。A4gnt(-/-) 小鼠的胃腺体黏液中完全缺乏αGlcNAc 表达。令人惊讶的是，所有突变小鼠在没有幽门螺杆菌感染的情况下通过增生-发育不良-癌序列发展为胃腺癌。微阵列和定量 RT-PCR 分析显示，A4gnt(-/-) 小鼠胃黏膜中编码炎症趋化因子配体、促炎细胞因子和生长因子的基因上调，如 Ccl2、Il-11 和 Hgf。进一步支持这种 O-聚糖在癌症进展中的重要作用，我们还观察到人类胃腺癌和腺瘤中αGlcNAc 显著减少。我们的结果表明，体内缺乏αGlcNAc 通过炎症相关途径触发胃肿瘤发生。因此，αGlcNAc 末端的胃黏液在通过抑制幽门螺杆菌感染预防胃癌和抑制肿瘤促进炎症方面发挥双重作用。
