Snail regulates Nanog status during the epithelial-mesenchymal transition via the Smad1/Akt/GSK3β signaling pathway in non-small-cell lung cancer.

Chen-Wei Liu,Huei-Wen Chen,Yu-Wen Cheng,Mao-Hsiung Yeng,Yi-Jen Peng,Ching-Hao Li,Po-Lin Liao,Jaw-Jou Kang

doi:10.18632/oncotarget.2006

Chen-Wei Liu, Huei-Wen Chen + Show 6 more

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https://doi.org/10.18632/oncotarget.2006

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Abstract

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.

Highlights

Lung cancer is the most common cause of cancer mortality in the world, with an estimated annual 1.3 million deaths worldwide [1]
Our results indicate that Nanog expression via the activation of the Smad1/Akt/ GSK3β pathway is required to sustain the cancer stem www.impactjournals.com/oncotarget cell-like traits generated by Snail-induced epithelial–mesenchymal transition (EMT)
We found that Snail was mainly expressed in nuclei and that Snail expression showed significant correlation with age (p = 0.041), cell type (p = 0.039), clinicopathological grade (p = 0.012), and tumor status (p = 0.0429; Table 1), indicating that Snail has a critical role in directing tumors toward malignancy

Summary

Introduction

Lung cancer is the most common cause of cancer mortality in the world, with an estimated annual 1.3 million deaths worldwide [1]. It is often diagnosed at an advanced stage and has a poor prognosis. Non-smallcell lung cancer (NSCLC), like nearly 90% of human cancers, is epithelial in origin, and the increased motility and invasiveness of cancer cells are reminiscent of the epithelial–mesenchymal transition (EMT). Accumulating evidence suggests that EMT can occur during tumor www.impactjournals.com/oncotarget Total Age > 60.

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