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
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14-3-3β/GSK-3β/β-catenin 复合物调节 HUVEC 中 27-羟基胆固醇诱导的 EndMT 并促进乳腺癌细胞的迁移
DOI：
10.1007/s10565-020-09564-y
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Li Zhong
中科院分区：
文献类型：
--
作者：
Zhen Jing;Jiao kailin;Yang Keke;Wu Maoxuan;Zhou Qian;Yang Bingmo;Xiao Wei;Hu Chunyan;Zhou Ming;Li Zhong
内皮-间充质转化（EndMT）是指内皮细胞形态向间充质细胞形态转变，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）是胆固醇的代谢产物，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。我们之前已经证明27-HC促进EndMT;然而，其潜在机制仍需进一步探索。我们研究了14-3-3η/GSK-3β/β-catenin复合物在EndMT中的作用。我们的研究结果表明，27-HC诱导HUVECs氧化应激，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-catenin的增加和核转位，最终诱导EndMT。用N-乙酰半胱氨酸（NAC）处理阻断27-HC诱导的ROS产生和p38信号通路激活，阻止β-catenin从结合中释放，并抑制EndMT。阻断ROS产生或p38信号或敲低14-3-3η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-catenin复合物之间的相互作用是必需的，并且作为衔接子将上游激酶信号传递到下游信号，从而促进EndMT和乳腺癌细胞迁移。
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.
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