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ROS-Nrf2 Pathway Mediates the Development of TGF-b1-Induced Epithelial-Mesenchymal Transition Through the Interaction with Notch Signaling

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A3805 - ROS-Nrf2 Pathway Mediates the Development of TGF-b1-Induced Epithelial-Mesenchymal Transition Through the Interaction with Notch Signaling
Author Block: Y. Matsuno, M. Matsuyama, T. Kiwamoto, Y. Morishima, Y. Ishii, N. Hizawa; Respiratory Medicine, University of Tsukuba, Tsukuba, Japan.
RATIONALE: Emerging evidence demonstrates the role of reactive oxygen species (ROS) as second messengers in various cellular signaling pathways. Intracellular ROS levels are regulated by Nrf2-dependent induction of a range of antioxidant genes expression. TGF-b1 induces epithelial-mesenchymal transition (EMT) via Notch signaling induction of a transcription factor snai1 in A549 cells. While ROS is generated by TGF-b1, its role in the development of EMT remains unclear. We hypothesized that ROS-Nrf2 is involved in TGF-b1 signaling and thereby in the development of EMT.
METHODS: A549 cells were treated with TGF-b1 to induce EMT, which is verified by analyzing the expression of epithelial (E cadherin) and mesenchymal (N cadherin, vimentin) markers and snai1. Intracellular ROS levels were detected using DCFDA. Real-time PCR and western blotting were used to analyze the expression of molecules involved in Nrf2 and Notch signaling. To clarify the role of ROS, A549 cells were treated with N-acetyl cysteine (NAC) to decrease ROS production. To determine the role of Nrf2, expression of Nrf2 was inhibited by transfecting siRNA targeting Nrf2 or by overexpressing Keap1, which facilitates the degradation of Nrf2.
RESULTS: TGF-b1 increased ROS levels and induced Nrf2 activation as well as its target gene expression. Reduction of ROS levels by NAC suppressed Nrf2 activation, which is accompanied by the attenuation of Notch signaling activation and EMT induction. Similarly, inhibition of Nrf2 expression ameliorated Notch signaling activation and EMT induction.
CONCLUSION: ROS-Nrf2 pathway is activated by TGF-b1 and plays critical role in the development of EMT by modulating Notch signaling pathway.
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