Snail regulates Nanog status during the epithelial-mesenchymal transition via the Smad1/Akt/GSK3β signaling pathway in non-small-cell lung cancer.
Snail regulates Nanog status during the epithelial-mesenchymal transition via the Smad1/Akt/GSK3β signaling pathway in non-small-cell lung cancer.
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DOI：
10.18632/oncotarget.2006
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发表时间：
2014-06-15
期刊：
影响因子：
--
通讯作者：
Yeng MH
中科院分区：
文献类型：
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作者：
Liu CW;Li CH;Peng YJ;Cheng YW;Chen HW;Liao PL;Kang JJ;Yeng MH
上皮-间质转化（EMT）是肿瘤转移的关键步骤，在具有干细胞样特性的转化癌细胞中非常重要。在本研究中，我们建立了一个Snail过表达的非小细胞肺癌（NSCLC）细胞模型，并探讨其潜在的机制。我们还确定了有助于Snail调节Nanog表达的下游分子信号通路。我们的数据显示，高水平的Snail表达与NSCLC中的转移和高水平的Nanog表达相关。表达Snail的NSCLC细胞的特征在于活跃的EMT特征，并且表现出增加的迁移能力、化学抗性、球体形成和干细胞样性质。我们还研究了Snail介导的Nanog表达所需的信号。我们的数据表明，LY 294002，SB 431542，LDN 193189和Noggin预处理抑制EMT期间Snail诱导的Nanog表达。该研究显示Snail表达与Smad 1、Akt和GSK 3 β的磷酸化之间存在显著相关性。此外，SB 431542、LDN 193189或Noggin预处理可阻止Snail诱导的Smad 1和Akt过度活化，并重新激活GSK 3 β。此外，LY 294002预处理可防止Akt过度活化并重新激活GSK 3 β，而不改变Smad 1的活化。这些发现为Snail在EMT期间在NSCLC中的重要作用提供了新的机制见解，并为NSCLC提供了潜在的有用治疗靶点。
The epithelial–mesenchymal transition (EMT), a crucial step in cancer metastasis, is important in transformed cancer cells with stem cell-like properties. In this study, we established a Snail-overexpressing cell model for non-small-cell lung cancer (NSCLC) and investigated its underlying mechanism. We also identified the downstream molecular signaling pathway that contributes to the role of Snail in regulating Nanog expression. Our data shows that high levels of Snail expression correlate with metastasis and high levels of Nanog expression in NSCLC. NSCLC cells expressing Snail are characterized by active EMT characteristics and exhibit an increased ability to migrate, chemoresistance, sphere formation, and stem cell-like properties. We also investigated the signals required for Snail-mediated Nanog expression. Our data demonstrate that LY294002, SB431542, LDN193189, and Noggin pretreatment inhibit Snail-induced Nanog expression during EMT. This study shows a significant correlation between Snail expression and phosphorylation of Smad1, Akt, and GSK3β. In addition, pretreatment with SB431542, LDN193189, or Noggin prevented Snail-induced Smad1 and Akt hyperactivation and reactivated GSK3β. Moreover, LY294002 pretreatment prevented Akt hyperactivation and reactivated GSK3β without altering Smad1 activation. These findings provide a novel mechanistic insight into the important role of Snail in NSCLC during EMT and indicate potentially useful therapeutic targets for NSCLC.