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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Chen-Wei Liu1, Ching-Hao Li2,3, Yi-Jen Peng4, Yu-Wen Cheng5, Huei-Wen Chen6, Po-Lin Liao5,6, Jaw-Jou Kang6 and Mao-Hsiung Yeng7
1 Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
2 Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
3 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
4 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
5 School of Pharmacy, Taipei Medical University, Taipei, Taiwan
6 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
7 Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan
Mao-Hsiung Yen, email:
Jaw-Jou Kang, email:
Keywords: Snail, Nanog, epithelial–mesenchymal transition, cancer stem cell, Smad, Akt, Noggin, non-small-cell lung cancer
Received: April 7, 2014 Accepted: May 24, 2014 Published: May 26, 2014
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.
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