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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 Biology and Toxicology ( IF 5.3 ) Pub Date : 2020-11-01 , 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 1
Affiliation  

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.



中文翻译:

14-3-3η/GSK-3β/β-catenin复合物调节HUVECs中27-羟基胆固醇诱导的EndMT并促进乳腺癌细胞的迁移

内皮-间质转化(EndMT)是内皮细胞形态向间充质细胞形态的转变,伴随内皮功能下降和间充质功能增强,促进肿瘤进展和肿瘤细胞侵袭转移。27-羟基胆固醇 (27-HC) 是一种胆固醇代谢物,在人体血液中含量很高。27-HC 促进乳腺癌细胞增殖、侵袭和迁移。我们之前表明 27-HC 促进 EndMT ;但是,其潜在机制仍需进一步探索。我们研究了 14-3-3η/GSK-3β/β-连环蛋白复合物在 EndMT 中的作用。我们的研究结果表明,27-HC 在 HUVECs 中诱导氧化应激并激活 p38 信号通路,从而抑制 14-3-3η/GSK-3β/β-catenin 的结合,促进游离β-连环蛋白的增加和核转位,最终诱导EndMT。N-乙酰半胱氨酸 (NAC) 处理可阻断 27-HC 诱导的 ROS 生成和 p38 信号通路激活,阻止 β-连环蛋白从结合中释放,并抑制 EndMT。阻断 ROS 产生或 p38 信号传导或敲除 14-3-3η 可抑制 27-HC 诱导的 EndMT 并抑制乳腺癌细胞转移。这些发现表明 14-3-3η 对于 p38 激酶和 GSK-3β/β-连环蛋白复合物之间的相互作用是必需的,并作为将上游激酶信号传递到下游信号的接头,从而促进 EndMT 和乳腺癌细胞迁移. 阻止 β-连环蛋白从结合中释放,并抑制 EndMT。阻断 ROS 产生或 p38 信号传导或敲除 14-3-3η 可抑制 27-HC 诱导的 EndMT 并抑制乳腺癌细胞转移。这些发现表明 14-3-3η 对于 p38 激酶和 GSK-3β/β-连环蛋白复合物之间的相互作用是必需的,并作为将上游激酶信号传递到下游信号的接头,从而促进 EndMT 和乳腺癌细胞迁移. 阻止 β-连环蛋白从结合中释放,并抑制 EndMT。阻断 ROS 产生或 p38 信号传导或敲除 14-3-3η 可抑制 27-HC 诱导的 EndMT 并抑制乳腺癌细胞转移。这些发现表明 14-3-3η 对于 p38 激酶和 GSK-3β/β-连环蛋白复合物之间的相互作用是必需的,并作为将上游激酶信号传递到下游信号的接头,从而促进 EndMT 和乳腺癌细胞迁移.

更新日期:2020-11-02
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