Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells

Keisuke Oguma, Hiroko Oshima, Masahiro Aoki, Ryusei Uchio, Kazuhito Naka, Satoshi Nakamura, Atsushi Hirao, Hideyuki Saya, Makoto Mark Taketo, Masanobu Oshima

研究成果: Article査読

240 被引用数 (Scopus)

抄録

The activation of Wnt/β-catenin signalling has an important function in gastrointestinal tumorigenesis. It has been suggested that the promotion of Wnt/β-catenin activity beyond the threshold is important for carcinogenesis. We herein investigated the role of macrophages in the promotion of Wnt/β-catenin activity in gastric tumorigenesis. We found β-catenin nuclear accumulation in macrophage-infiltrated dysplastic mucosa of the K19-Wnt1 mouse stomach. Moreover, macrophage depletion in Apc Δ716 mice resulted in the suppression of intestinal tumorigenesis. These results suggested the role of macrophages in the activation of Wnt/β-catenin signalling, which thus leads to tumour development. Importantly, the conditioned medium of activated macrophages promoted Wnt/β-catenin signalling in gastric cancer cells, which was suppressed by the inhibition of tumour necrosis factor (TNF)-α. Furthermore, treatment with TNF-α induced glycogen synthase kinase 3β (GSK3β) phosphorylation, which resulted in the stabilization of β-catenin. We also found that Helicobacter infection in the K19-Wnt1 mouse stomach caused mucosal macrophage infiltration and nuclear β-catenin accumulation. These results suggest that macrophage-derived TNF-α promotes Wnt/β-catenin signalling through inhibition of GSK3β, which may contribute to tumour development in the gastric mucosa.

本文言語English
ページ(範囲)1671-1681
ページ数11
ジャーナルEMBO Journal
27
12
DOI
出版ステータスPublished - 18-06-2008
外部発表はい

All Science Journal Classification (ASJC) codes

  • 神経科学(全般)
  • 分子生物学
  • 生化学、遺伝学、分子生物学(全般)
  • 免疫学および微生物学(全般)

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