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  2. The 14-3-3η/GSK-3β/β-catenin complex regulates EndMT induced by 27-hydroxycholesterol in HUVECs and promotes the migration of breast cancer cells

The 14-3-3η/GSK-3β/β-catenin complex regulates EndMT induced by 27-hydroxycholesterol in HUVECs and promotes the migration of breast cancer cells

  • Cell Biol Toxicol. 2021 Aug;37(4):515-529. doi: 10.1007/s10565-020-09564-y.
Jing Zhen 1 Kailin Jiao 1 Keke Yang 1 Maoxuan Wu 1 Qian Zhou 1 Bingmo Yang 1 Wei Xiao 1 Chunyan Hu 1 Ming Zhou 1 Zhong Li 2
Affiliations

Affiliations

  • 1 The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
  • 2 The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. lz-ny@njmu.edu.cn.
Abstract

Endothelial-mesenchymal transition (EndMT) is the transformation of endothelial cell morphology to mesenchymal cell morphology, accompanied by decline of endothelial function and enhancement of mesenchymal function, which promotes tumor progression and tumor cell invasion and metastasis. 27-Hydroxycholesterol (27-HC) is a Cholesterol metabolite, which has a high content in human blood. 27-HC promotes breast Cancer cell proliferation, invasion, and migration. We previously showed that 27-HC promotes EndMT; however, the underlying mechanism still needs to be further explored. We studied the role of the 14-3-3η/GSK-3β/β-catenin complex in EndMT. Our results show that 27-HC induces oxidative stress in HUVECs and activates the p38 signaling pathway, thereby inhibiting the binding of 14-3-3η/GSK-3β/β-catenin, promoting the increase of free β-catenin and nuclear translocation, and finally inducing EndMT. Treatment with N-acetylcysteine (NAC) blocked 27-HC-induced ROS generation and p38 signaling pathway activation, prevented β-catenin from release from binding, and inhibited EndMT. Blocking ROS production or p38 signaling or knocking down 14-3-3η inhibited 27-HC-induced EndMT and inhibited breast Cancer cell metastasis. These findings indicate 14-3-3η is necessary for interactions between the p38 kinase and the GSK-3β/β-catenin complex and serves as an adaptor to transmit the upstream kinase signal to the downstream signal, thereby promoting EndMT and breast Cancer cell migration.

Keywords

14-3-3η; 27-HC; EndMT; GSK-3β; β-catenin.

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