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NRF2 level is negatively correlated with TGF-β1-induced lung cancer motility and migration via NOX4-ROS signaling

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Transforming growth factor-β1 (TGF-β1) is a multifaceted factor in cancer biology that regulates cell proliferation and migration. Overactivation of nuclear factor erythroid 2-like 2 (NFE2L2; NRF2) in cancers has been associated with facilitated tumor growth and therapy resistance; however, role in cancer migration has not been clearly explained yet. In this study, we investigated the role of NRF2 on TGF-β1-induced cell motility/migration. In NRF2-silenced lung cancer A549 cells, both basal and TGF-β1-inducible cell motility/migration increased compared to those in A549. SMAD transcription activity and phosphorylated SMAD2/3 levels were higher in TGF-β1-treated NRF2-low A549 cells than those in A549. Notably, the levels of reactive oxygen species (ROS) that were elevated by TGF-β1 treatment were higher in the NRF2-low A549 than those in control cells, and treatment with ROS scavenger blocked TGF-β1-induced cell motility. As an underlying molecular link, NADPH oxidase 4 (NOX4) was associated with higher ROS elevation and cell motility of NRF2-low A549. NOX4 and TGF-β1-inducible NOX4 levels were higher in NRF2-low A549 cells than those in A549. Moreover, the pharmacological inhibition of NOX4 blocked the TGF-β1-induced motility of NRF2-low A549 cells. Collectively, these results indicate that TGF-β1-induced cell motility/migration is facilitated in NRF2-inhibited lung cancer cells and that high levels of NOX4/ROS are associated with enhanced motility/migration.

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This study was financially supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean Government (2018R1A2A1A05078894, 2018R1A6A1A03025108). This study was also supported by the BK21FOUR program and by the Research Fund 2020 of The Catholic University of Korea.

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Correspondence to Mi-Kyoung Kwak.

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Ryu, D., Lee, JH. & Kwak, MK. NRF2 level is negatively correlated with TGF-β1-induced lung cancer motility and migration via NOX4-ROS signaling. Arch. Pharm. Res. 43, 1297–1310 (2020).

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