Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells.
The activation of Wnt/beta-catenin signalling has an important function in gastrointestinal tumorigenesis. It has been suggested that the promotion of Wnt/beta-catenin activity beyond the threshold is important for carcinogenesis. We herein investigated the role of macrophages in the promotion of Wnt/beta-catenin activity in gastric tumorigenesis. We found beta-catenin nuclear accumulation in macrophage-infiltrated dysplastic mucosa of the K19-Wnt1 mouse stomach. Moreover, macrophage depletion in Apc(Delta716) mice resulted in the suppression of intestinal tumorigenesis. These results suggested the role of macrophages in the activation of Wnt/beta-catenin signalling, which thus leads to tumour development. Importantly, the conditioned medium of activated macrophages promoted Wnt/beta-catenin signalling in gastric cancer cells, which was suppressed by the inhibition of tumour necrosis factor (TNF)-alpha. Furthermore, treatment with TNF-alpha induced glycogen synthase kinase 3beta (GSK3beta) phosphorylation, which resulted in the stabilization of beta-catenin. We also found that Helicobacter infection in the K19-Wnt1 mouse stomach caused mucosal macrophage infiltration and nuclear beta-catenin accumulation. These results suggest that macrophage-derived TNF-alpha promotes Wnt/beta-catenin signalling through inhibition of GSK3beta, which may contribute to tumour development in the gastric mucosa.
Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Keisuke
K
Oguma
Hiroko
H
Oshima
Masahiro
M
Aoki
Ryusei
R
Uchio
Kazuhito
K
Naka
Satoshi
S
Nakamura
Atsushi
A
Hirao
Hideyuki
H
Saya
Makoto Mark
MM
Taketo
Masanobu
M
Oshima
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004847:Epithelial Cells / Q000382:microbiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D016481:Helicobacter Infections / Q000473:pathology; D006801:Humans; D008262:Macrophage Activation; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction; D013270:Stomach / Q000382:microbiology / Q000473:pathology; D013274:Stomach Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051155:Wnt1 Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051155:Wnt1 Protein; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3