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

被引：245

作者：

Oguma, Keisuke ^{[1
]}

Oshima, Hiroko ^{[1
]}

Aoki, Masahiro ^{[2
]}

Uchio, Ryusei ^{[1
]}

Naka, Kazuhito ^{[3
]}

Nakamura, Satoshi ^{[4
]}

Hirao, Atsushi ^{[3
]}

Saya, Hideyuki ^{[5
]}

Taketo, Makoto Mark

Oshima, Masanobu ^{[1
]}

机构：

[1] Kanazawa Univ, Canc Res Inst, Div Genet, Kanazawa, Ishikawa 9200934, Japan

[2] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Kyoto, Japan

[3] Kanazawa Univ, Canc Res Inst, Div Mol Genet, Kanazawa, Ishikawa, Japan

[4] Link Genom, Dept Biomed Res & Dev, Tokyo, Japan

[5] Keio Univ, Sch Med, Inst Adv Med Res, Div Gene Regulat, Tokyo, Japan

来源：

EMBO JOURNAL | 2008年 / 27卷 / 12期

关键词：

gastric cancer; inflammation; macrophage; tumour necrosis factor-alpha; Wnt;

D O I：

10.1038/emboj.2008.105

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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(Delta 716) 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 3 beta (GSK3 beta) 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 GSK3 beta, which may contribute to tumour development in the gastric mucosa.

引用

页码：1671 / 1681

页数：11

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