Essential role of gastric gland mucin in preventing gastric cancer in mice.
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.
Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Fumitoshi
F
Karasawa
Akira
A
Shiota
Yukinobu
Y
Goso
Motohiro
M
Kobayashi
Yoshiko
Y
Sato
Junya
J
Masumoto
Maiko
M
Fujiwara
Shuichi
S
Yokosawa
Takashi
T
Muraki
Shinichi
S
Miyagawa
Masatsugu
M
Ueda
Michiko N
MN
Fukuda
Minoru
M
Fukuda
Kazuhiko
K
Ishihara
Jun
J
Nakayama
D000230:Adenocarcinoma / Q000378:metabolism; D000236:Adenoma / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D049109:Cell Proliferation; D018450:Disease Progression; D005752:Gastric Mucins / Q000378:metabolism*; D016480:Helicobacter pylori / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008954:Models, Biological; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D013274:Stomach Neoplasms / Q000378:metabolism*
D005752:Gastric Mucins; D017351:N-Acetylglucosaminyltransferases; C038111:alpha-1,3-mannosylglycoprotein beta-1,4-N-acetylglucosaminyltransferase