Notch4 promotes gastric cancer growth through activation of Wnt1/β-catenin signaling
Notch4 promotes gastric cancer growth through activation of Wnt1/β-catenin signaling
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DOI：
10.1007/s11010-014-2304-z
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发表时间：
2015-03-01
影响因子：
4.3
通讯作者：
Yao, Jun
中科院分区：
文献类型：
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作者：
Qian, Cuijuan;Liu, Fuqiang;Yao, Jun
胃癌是世界上最常见的恶性肿瘤之一。发现与GC相关的新生物标志物可能为降低GC的严重程度提供机会。Notch 4是哺乳动物Notch受体家族成员之一，在多种肿瘤的发生发展中起重要作用。然而，Notch 4在胃癌中的确切功能和机制仍不清楚。为了解决这个问题，我们研究了Notch 4是否可能参与GC进展。我们发现Notch 4通过过量表达外源性Notch 4胞内结构域（ICN 4）而被激活，并且Notch 4激活促进体外和体内GC生长，而使用ICN 4 siRNA抑制Notch 4则具有相反的效果。此外，Notch 4激活诱导GC细胞中Wnt 1、β-连环蛋白和下游靶基因c-Myc和细胞周期蛋白D1的表达和激活，而Notch 4抑制则具有相反的作用。此外，通过siRNA消耗β-连环蛋白减弱了Notch 4活化诱导的细胞增殖。因此，我们的研究结果表明，Notch 4激活Wnt 1/β-catenin信号转导来调节GC生长。
Gastric cancer (GC) is one of the most common cancers and lethal malignancies in the world. Discovering novel biomarkers that correlate with GC may provide opportunities to reduce the severity of GC. As one of Notch receptor family members in mammals, Notch4 plays an important role in carcinogenesis of several tumors. However, the precise function and mechanism of Notch4 in GC remain undefined. To address this question, we investigated whether Notch4 could be involved in GC progression. We found that Notch4 was activated by overexpressing exogenous intracellular domain of Notch4 (ICN4), and Notch4 activation promoted GC growth in vitro and in vivo, while Notch4 inhibition using ICN4 siRNA had opposite effects. In addition, Notch4 activation induced expression and activation of Wnt1, beta-catenin and downstream target genes, c-Myc and cyclin D1, in GC cells, while Notch4 inhibition had opposite effects. Moreover, beta-catenin depletion by siRNA attenuated cell proliferation induced by Notch4 activation. Therefore, our results revealed that Notch4 activates Wnt1/beta-catenin signaling to regulate GC growth.