ROS-Nrf2 pathway mediates the development of TGF-β1-induced epithelial-mesenchymal transition through the activation of Notch signaling
ROS-Nrf2 pathway mediates the development of TGF-β1-induced epithelial-mesenchymal transition through the activation of Notch signaling
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DOI：
10.1016/j.ejcb.2021.151181
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发表时间：
2021-11-08
影响因子：
6.6
通讯作者：
Hizawa, Nobuyuki
中科院分区：
文献类型：
--
作者：
Yazaki, Kai;Matsuno, Yosuke;Hizawa, Nobuyuki
上皮-间质转化（EMT）是上皮细胞转化以获得间质表型的细胞过程。越来越多的证据表明EMT参与恶性疾病的进展。 Notch 信号通过 Snail 的直接转录激活介导 TGF-β 1 诱导的 EMT。然而，TGF-β1 激活 Notch 信号传导的分子机制仍不清楚。在这项研究中，我们展示了活性氧 (ROS)-Nrf2 通路在 TGF-β 1 诱导的 Notch 信号激活和 EMT 发展中的关键作用。 TGF-β 1 通过 ROS 产生诱导 Nrf2 激活。通过 N-乙酰半胱氨酸降低 ROS 水平或通过小干扰 RNA 敲低 Nrf2 来抑制 Nrf2 激活，可减弱 Notch 信号传导激活和 EMT 发展。 TGF-β1 通过 Nrf2 依赖性启动子激活诱导 Notch4 转录。总之，我们的研究表明 ROS-Nrf2 通路通过激活 Notch 信号传导介导 TGF-β 1 诱导的 EMT 的发展。
Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells transform to acquire mesenchymal phenotypes. Accumulating evidence indicate the involvement of EMT in the progression of malignant diseases. Notch signaling mediates TGF-beta 1-induced EMT through direct transcriptional activation of Snail. The molecular mechanism how TGF-beta 1 activates Notch signaling, however, remains unknown. In this study, we show a pivotal role for reactive oxygen species (ROS)-Nrf2 pathway in TGF-beta 1-induced Notch signaling activation and EMT development. TGF-beta 1 induces Nrf2 activation through ROS production. Inhibiting Nrf2 activation either by reducing ROS levels by N-acetylcysteine or by knocking down of Nrf2 by small interfering RNA attenuated both Notch signaling activation and EMT development. TGF-beta 1 induced the transcription of Notch4 via Nrf2-dependent promoter activation. In conclusion, our study indicates the ROS-Nrf2 pathway mediates the development of TGF-beta 1-induced EMT through the activation of Notch signaling.