Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells.
Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells.
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DOI：
10.1038/emboj.2008.105
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发表时间：
2008-06-18
期刊：
影响因子：
11.4
通讯作者：
Oshima, Masanobu
中科院分区：
文献类型：
--
作者：
Oguma, Keisuke;Oshima, Hiroko;Aoki, Masahiro;Uchio, Ryusei;Naka, Kazuhito;Nakamura, Satoshi;Hirao, Atsushi;Saya, Hideyuki;Taketo, Makoto Mark;Oshima, Masanobu
Wnt/β-Catenin信号通路的激活在胃肠道肿瘤的发生发展中起着重要作用。已有研究表明，超过阈值的WNT/β-连环蛋白活性升高在肿瘤发生中具有重要意义。在此，我们研究了巨噬细胞在促进WNT/β-连环蛋白活性在胃肿瘤发生中的作用。我们发现β-连环蛋白在K19-WNT1小鼠胃的巨噬细胞浸润性发育不良粘膜中有核聚集。此外，APCΔ716小鼠体内巨噬细胞的耗尽抑制了肠道肿瘤的发生。这些结果提示巨噬细胞在激活WNT/β-连环蛋白信号通路中的作用，从而导致肿瘤发展。重要的是，激活的巨噬细胞条件培养液促进了胃癌细胞的WNT/β-连环蛋白信号转导，而这种信号转导被肿瘤坏死因子-α抑制。此外，肿瘤坏死因子-α可诱导糖原合成酶ββ的磷酸化，从而使β-连环蛋白稳定。我们还发现，K19-WNT1小鼠胃中的幽门螺杆菌感染引起了粘膜巨噬细胞的浸润和核β-连环蛋白的聚集。这些结果表明，巨噬细胞来源的肿瘤坏死因子-α通过抑制GSK3β而促进WNT/GSK3-连环蛋白信号转导，这可能与胃粘膜肿瘤的发生有关。
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 ApcΔ716 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.
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影响因子：
8
作者：
Nojima, M.;Suzuki, H.;Shinomura, Y.
通讯作者：
Shinomura, Y.
影响因子：
82.9
作者：
Sonoshita, M;Takaku, K;Taketo, MM
通讯作者：
Taketo, MM
影响因子：
2.8
作者：
Brabletz, T;Jung, A;Kirchner, T
通讯作者：
Kirchner, T
DOI：
10.1073/pnas.0405979102
发表时间：
2005-01-04
影响因子：
11.1
作者：
Pull, SL;Doherty, JM;Stappenbeck, TS
通讯作者：
Stappenbeck, TS
影响因子：
29.4
作者：
Howlett, M;Judd, LM;Giraud, AS
通讯作者：
Giraud, AS