Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity
Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity
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DOI：
10.1038/ncomms5423
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发表时间：
2014-07-01
影响因子：
16.6
通讯作者：
Lee, Yong Chan
中科院分区：
文献类型：
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作者：
Lee, Da-Gyum;Kim, Hyun Sil;Lee, Yong Chan
细胞毒素相关基因 A (CagA) 是一种癌蛋白，也是幽门螺杆菌的主要毒力因子。 CagA 通过 IV 型分泌系统递送至胃上皮细胞并引起细胞转化。伴随上皮-间质转化（EMT）的上皮粘附丧失是胃癌的一个标志。尽管 CagA 是胃癌的致病因素，但 CagA 与相关 EMT 之间的联系尚未阐明。在这里，我们发现 CagA 通过稳定 Snail（E-钙粘蛋白表达的转录抑制因子）来诱导 EMT。从机制上讲，我们表明 CagA 以类似于 Axin 的方式结合 GSK-3，并导致其转变为不溶性部分，从而导致 GSK-3 活性降低。我们还发现临床样本中幽门螺杆菌感染的上皮细胞中 Snail 蛋白的水平有所增加。这些结果表明，幽门螺杆菌 CagA 作为一种致病性支架蛋白，通过消耗 GSK-3 诱导 Snail 介导的 EMT。
Cytotoxin-associated gene A (CagA) is an oncoprotein and a major virulence factor of H. pylori. CagA is delivered into gastric epithelial cells via a type IV secretion system and causes cellular transformation. The loss of epithelial adhesion that accompanies the epithelial-mesenchymal transition (EMT) is a hallmark of gastric cancer. Although CagA is a causal factor in gastric cancer, the link between CagA and the associated EMT has not been elucidated. Here, we show that CagA induces the EMT by stabilizing Snail, a transcriptional repressor of E-cadherin expression. Mechanistically we show that CagA binds GSK-3 in a manner similar to Axin and causes it to shift to an insoluble fraction, resulting in reduced GSK-3 activity. We also find that the level of Snail protein is increased in H. pylori infected epithelium in clinical samples. These results suggest that H. pylori CagA acts as a pathogenic scaffold protein that induces a Snail-mediated EMT via the depletion of GSK-3.