RRC ID 67959
著者 Oguma K, Oshima H, Aoki M, Uchio R, Naka K, Nakamura S, Hirao A, Saya H, Taketo MM, Oshima M.
タイトル Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells.
ジャーナル EMBO J
Abstract 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.
巻・号 27(12)
ページ 1671-81
公開日 2008-6-18
DOI 10.1038/emboj.2008.105
PII emboj2008105
PMID 18511911
PMC PMC2413189
MeSH Adenomatous Polyposis Coli Protein / metabolism Animals Cell Line, Tumor Cell Nucleus / metabolism Epithelial Cells / microbiology Glycogen Synthase Kinase 3 / antagonists & inhibitors Glycogen Synthase Kinase 3 beta Helicobacter Infections / pathology Humans Macrophage Activation* Mice Mice, Transgenic Mutation / genetics NF-kappa B / metabolism Phosphorylation Precancerous Conditions / enzymology Precancerous Conditions / pathology Signal Transduction* Stomach / microbiology Stomach / pathology Stomach Neoplasms / enzymology Stomach Neoplasms / metabolism* Stomach Neoplasms / pathology Tumor Necrosis Factor-alpha / metabolism* Wnt1 Protein / metabolism* beta Catenin / metabolism
IF 9.889
リソース情報
ヒト・動物細胞 RAW 264(RCB0535)