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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.
Highlights
Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 80% of all lung cancers [1]
The results indicated that Nuclear factor E2 related factor 2 (Nrf2) and Notch1 are involved in ionizing radiation (IR) responses and Nrf2 is dependent on the proteasome-mediated protein degradation pathway
We showed that IR induces Nrf2 activation, matrix metalloproteinase (MMP)-2/9 expression, N-cadherin expression and apoptosis, but reduces E-cadherin and subsequently contributes to NSCLC metastasis in an Nrf2-related mechanism
Summary
Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 80% of all lung cancers [1]. Radiotherapy is routinely used for lung cancer treatment and is effective as a curative modality [2]. With the continuous improvement of diagnostic and therapeutic approaches, most patients with early stage NSCLC have been cured successfully. The 5-year survival rate for advanced stage NSCLC is as low as 15% [3], as these patients present with metastatic disease [4]. The mechanisms underlying lung cancer metastasis remain elusive. There is an urgent need to better understand the molecular mechanisms associated with radiation-induced carcinogenesis to improve radiotherapy treatments for lung cancer patients
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