Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2018; 9:31787.

Halofuginone inhibits radiotherapy-induced epithelial-mesenchymal transition in lung cancer

Yang Chen, Weishuai Liu, Peng Wang, Hailing Hou, Ningbo Liu, Linlin Gong, Youyou Wang, Kai Ji, Lujun Zhao _ and Ping Wang

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Oncotarget. 2016; 7:71341-71352. https://doi.org/10.18632/oncotarget.11217

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Abstract

Yang Chen1,*, Weishuai Liu2,*, Peng Wang3, Hailing Hou1, Ningbo Liu1, Linlin Gong1, Youyou Wang1, Kai Ji2, Lujun Zhao1, Ping Wang1

1Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China

2Department of Pain Management, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research, Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China

3Department of Radiation Oncology, Peking University International Hospital, Beijing 102206, China

*These authors have contributed equally to this work

Correspondence to:

Lujun Zhao, email: zhaolujun@tjmuch.com

Keywords: epithelial-mesenchymal transition (EMT), halofuginone, transforming growth factor-β (TGF-β1), radiotherapy, lung cancer

Received: April 09, 2016     Accepted: July 27, 2016     Published: August 11, 2016

ABSTRACT

Radiotherapy is used to treat many different human tumors. Paradoxically, radiation can activate TGF-β1 signaling and induce the epithelial-mesenchymal transition (EMT), which is associated with enhanced tumor progression. This study investigated the inhibitory effects of halofuginone, a plant-derived alkaloid that has been shown to inhibit TGF-β1 signaling, on radiation-induced EMT and explored the underlying mechanisms using a Lewis lung carcinoma (LLC) xenograft model. The cells and animals were divided into five treatment groups: Normal Control (NC), Halofuginone alone (HF), Radiotherapy alone (RT), Radiotherapy combined with Halofuginone (RT+HF), and Radiotherapy combined with the TGF-β1 inhibitor SB431542 (RT+SB). Radiation induced EMT in lung cancer cells and xenografts, as evidenced by increased expression of the mesenchymal markers N-cadherin and Vimentin, and reduced expression of the epithelial markers E-cadherin and Cytokeratin. Further, radiotherapy treatment increased the migration and invasion of LLC cells. Halofuginone reversed the EMT induced by radiotherapy in vitro and in vivo, and inhibited the migration and invasion of LLC cells. In addition, TGF-β1/Smad signaling was activated by radiotherapy and the mRNA expression of Twist and Snail was elevated; this effect was reversed by halofuginone or the TGF-β1 inhibitor SB431542. Our results demonstrate that halofuginone inhibits radiation-induced EMT, and suggest that suppression of TGF-β1 signaling may be responsible for this effect.


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