The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling
The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling
复制标题
孤儿受体TR3通过下调Wnt信号传导抑制小鼠肠道肿瘤发生
DOI：
10.1136/gutjnl-2011-300783
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发表时间：
2012-05-01
期刊：
影响因子：
24.5
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
--
作者：
Chen, Hang-Zi;Liu, Qing-Feng;Wu, Qiao
Wnt信号通路参与细胞的稳态和发育。Wnt信号通路的失调与结直肠癌有关。孤儿核受体TR 3在增殖和凋亡中起重要作用。在这项研究中，我们研究了TR 3如何通过调节Wnt信号转导抑制肠道肿瘤发生。方法在Apcmin/+、Apcmin/+/TR 3 −/−和Apcmin/+/villin-TR 3小鼠中定量肠息肉。通过评估BAT-Gal报告菌株中的β-半乳糖苷酶活性来评价Wnt信号传导活性。使用TR 3激动剂胞孢素B来评估TR 3在肠肿瘤发生中的作用。在结直肠癌细胞中通过分子方法分析TR 3和β-catenin/TCF 4之间的串扰。在临床样品和结直肠癌细胞中评估糖原合成酶激酶（GSK）3β对TR 3的磷酸化以及GSK 3 β活性与TR 3磷酸化之间的相关性。结果TR 3能显著抑制Wnt信号通路的活性和肠上皮细胞的增殖。Apcmin/+/TR 3 −/−小鼠比Apcmin/+/TR 3 +/+小鼠产生更多的肠息肉，而在肠中TR 3的转基因过表达或用胞孢素B治疗Apcmin/+小鼠显著降低肠肿瘤数量。从机制上讲，TR 3破坏了β-连环蛋白和TCF 4在染色质上的结合，并促进了转录辅阻遏物向Wnt信号传导靶基因启动子的募集。然而，在大多数临床结直肠癌中，TR 3被GSK 3 β磷酸化，这减弱了TR 3对Wnt信号传导的抑制活性。结论TR 3是Wnt信号的负调控因子，可显著抑制Apcmin/+小鼠的肠道肿瘤发生。在临床结直肠癌中，TR 3的这种抑制作用可能通过GSK 3 β的磷酸化而矛盾地克服。
Aims Wnt signalling is involved in cellular homeostasis and development. Dysregulation of the Wnt signalling pathway has been linked to colorectal cancer. The orphan nuclear receptor TR3 plays important roles in proliferation and apoptosis. In this study, we investigated how TR3 suppresses intestinal tumorigenesis by regulating Wnt signalling. Methods Intestinal polyps were quantified in Apcmin/+, Apcmin/+/TR3−/− and Apcmin/+/villin-TR3 mice. Wnt signalling activity was evaluated by assessing β-galactosidase activity in a BAT-Gal reporter strain. The TR3 agonist cytosporone B was used to evaluate the role of TR3 in intestinal tumorigenesis. Crosstalk between TR3 and β-catenin/TCF4 was analysed by molecular methods in colorectal cancer cells. The phosphorylation of TR3 by glycogen synthase kinase (GSK) 3β and the correlation between GSK3β activity and TR3 phosphorylation were evaluated in clinical samples and colorectal cancer cells. Results TR3 was found to significantly suppress Wnt signalling activity and the proliferation of intestinal epithelial cells. Apcmin/+/TR3−/− mice developed more intestinal polyps than Apcmin/+/TR3+/+ mice, whereas either transgenic overexpression of TR3 in the intestine or treatment with cytosporone B in Apcmin/+ mice significantly decreased intestinal tumour number. Mechanistically, TR3 disrupted the association of β-catenin and TCF4 on chromatin and facilitated the recruitment of transcriptional co-repressors to the promoters of Wnt signalling target genes. However, TR3 was phosphorylated by GSK3β in most clinical colorectal cancers, which attenuated the inhibitory activity of TR3 towards Wnt signalling. Conclusions TR3 is a negative regulator of Wnt signalling and thus significantly suppresses intestinal tumorigenesis in Apcmin/+ mice. This inhibitory effect of TR3 may be paradoxically overcome through phosphorylation by GSK3β in clinical colorectal cancers.