Zhao Qiuyue, Mao Aihong, Guo Ruoshui, Zhang Liping, Yan Jiawei, Sun Chao, Tang Jinzhou, Ye Yancheng, Zhang Yanshan, Zhang Hong
Department of Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China.
Key Laboratory of Heavy Ion Radiation and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China.
Oncotarget. 2017 May 30;8(22):36603-36613. doi: 10.18632/oncotarget.16622.
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.
核因子E2相关因子2（Nrf2）是一种与肿瘤生长和辐射抗性相关的转录因子。经典的Notch信号通路对于维持非小细胞肺癌（NSCLC）也至关重要。异常的Nrf2和Notch信号已反复被证明促进NSCLC的转移。在此，我们表明辐射可诱导NSCLC中Nrf2和Notch1的表达。敲低Nrf2可增强NSCLC的放射敏感性并减少上皮-间质转化。重要的是，我们发现敲低Nrf2可显著降低辐射诱导的NSCLC侵袭，并显著增加E-钙黏蛋白，但降低N-钙黏蛋白和基质金属蛋白酶（MMP）-2/9的表达。我们发现敲低Notch1也会上调E-钙黏蛋白并抑制N-钙黏蛋白的表达。Nrf2有助于NSCLC细胞的转移特性，这种抑制与Notch1表达降低相关。这些结果表明，Nrf2和Notch1的下调协同抑制辐射诱导的NSCLC细胞的迁移和侵袭特性。
