Essential role of gastric gland mucin in preventing gastric cancer in mice
Fumitoshi Karasawa, … , Kazuhiko Ishihara, Jun Nakayama
Fumitoshi Karasawa, … , Kazuhiko Ishihara, Jun Nakayama
Published February 6, 2012
Citation Information: J Clin Invest. 2012;122(3):923-934. https://doi.org/10.1172/JCI59087.
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Essential role of gastric gland mucin in preventing gastric cancer in mice

Abstract

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.

Authors

Fumitoshi Karasawa, Akira Shiota, Yukinobu Goso, Motohiro Kobayashi, Yoshiko Sato, Junya Masumoto, Maiko Fujiwara, Shuichi Yokosawa, Takashi Muraki, Shinichi Miyagawa, Masatsugu Ueda, Michiko N. Fukuda, Minoru Fukuda, Kazuhiko Ishihara, Jun Nakayama

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Figure 4

Immunohistochemical expression of MUC6 and αGlcNAc in human pyloric mucosa, gastric differentiated-type adenocarcinoma, and gastric tubular adenoma.

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Immunohistochemical expression of MUC6 and αGlcNAc in human pyloric muco...
(A–E) Immunohistochemistry with monoclonal antibodies CLH5 for MUC6 and HIK1083 for αGlcNAc. (A) MUC6 expression in pyloric glands coincides with that of αGlcNAc in nonneoplastic pyloric mucosa. A normal region of the pyloric mucosa from a patient with undifferentiated-type adenocarcinoma is shown. By contrast, in gastric adenocarcinoma, αGlcNAc expression is reduced compared with that of MUC6. Shown are (B) moderate reduction of expression (patient no. 37 in Supplemental Table 1), (C) severe reduction of expression (patient no. 30 in Supplemental Table 1), and (D) no expression (patient no. 36 in Supplemental Table 1) of αGlcNAc in MUC6-positive adenocarcinoma cells. (E) In gastric adenoma, αGlcNAc expression is also reduced compared with that of MUC6: no expression of αGlcNAc is seen in MUC6-positive adenoma cells (patient no. 10 in Supplemental Table 2). Scale bar: 500 μm. Semiquantitation of MUC6 and αGlcNAc expression levels in (F) gastric adenocarcinoma and in (G) gastric adenoma. *P < 0.05; **P < 0.01 by Wilcoxon matched-pair test. Data represent the mean ± SEM. Expression level is scored based on the ratio of the number of immunoreactive tumor cells to the total number of tumor cells; 0, no positive cells; 1, less than one-third positive tumor cells; 2, less than two-thirds positive tumor cells; and 3, greater than two-thirds positive tumor cells.