Suppression of radiation-induced migration of non-small cell lung cancer through inhibition of Nrf2-Notch Axis

// Qiuyue Zhao 1, 2, 4, 5 , Aihong Mao 6 , Ruoshui Guo 7 , Liping Zhang 8 , Jiawei Yan 1, 2, 4, 5 , Chao Sun 1, 2, 4 , Jinzhou Tang 9 , Yancheng Ye 3 , Yanshan Zhang 3 and Hong Zhang 1, 2, 3, 4 1 Department of Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China 2 Key Laboratory of Heavy Ion Radiation and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China 3 Gansu Wuwei Institute of Medical Sciences, Gansu Province, Wuwei 733000, China 4 Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China 5 University of Chinese Academy of Sciences, Beijing 100039, China 6 Institute of Gansu Medical Science Research, Lanzhou 730000, China 7 South China Normal University, Guangzhou 510642, China 8 Northwest Normal University, Lanzhou 730000, China 9 Lan Zhou University, Lanzhou 730000, China Correspondence to: Hong Zhang, email: zhangh@impcas.ac.cn Keywords: Nrf2, ionizing radiation, Notch1, EMT, NSCLC Received: January 23, 2017 Accepted: March 09, 2017 Published: March 28, 2017 ABSTRACT Nuclear factor E2 related factor 2 (Nrf2) is a transcription factor that is associated with tumor growth and resistance to radiation. The canonical Notch signaling pathway is also crucial for maintaining non-small cell lung cancer (NSCLC). Aberrant Nrf2 and Notch signaling has repeatedly been showed to facilitate metastasis of NSCLC. Here, we show that radiation induce Nrf2 and Notch1 expression in NSCLC. Knockdown of Nrf2 enhanced radiosensitivity of NSCLC and reduced epithelial-to-mesenchymal transition. Importantly, we found that knockdown of Nrf2 dramatically decreased radiation-induced NSCLC invasion and significantly increased E-cadherin, but reduced N-cadherin and matrix metalloproteinase (MMP)-2/9 expression. We found that Notch1 knockdown also upregulated E-cadherin and suppressed N-cadherin expression. Nrf2 contributes to NSCLC cell metastatic properties and this inhibition correlated with reduced Notch1 expression. These results establish that Nrf2 and Notch1 downregulation synergistically inhibit radiation-induced migratory and invasive properties of NSCLC cells.