RRC ID |
67959
|
Author |
Oguma K, Oshima H, Aoki M, Uchio R, Naka K, Nakamura S, Hirao A, Saya H, Taketo MM, Oshima M.
|
Title |
Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells.
|
Journal |
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.
|
Volume |
27(12)
|
Pages |
1671-81
|
Published |
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
|
Resource |
Human and Animal Cells |
RAW 264(RCB0535) |