Activation of STAT-3 signalling by RECK downregulation via ROS is involved in the 27-hydroxycholesterol-induced invasion in breast cancer cells
Activation of STAT-3 signalling by RECK downregulation via ROS is involved in the 27-hydroxycholesterol-induced invasion in breast cancer cells
复制标题
RECK通过ROS下调激活STAT-3信号参与27-羟基胆固醇诱导的乳腺癌细胞侵袭
DOI：
10.1080/10715762.2020.1715965
复制
发表时间：
2020-01-27
影响因子：
3.3
通讯作者：
Li, Zhong
中科院分区：
文献类型：
--
作者：
Shen, Zhaoxia;Jiao, Kailin;Li, Zhong
摘要乳腺癌是世界范围内妇女的一种重要而常见的肿瘤。我们以前发现，27-羟基胆固醇（27 HC）促进乳腺癌细胞的侵袭和迁移，并通过活性氧（ROS）激活信号转导和转录激活因子3（STAT-3）信号转导。然而，ROS对STAT-3信号转导的调节需要进一步探索。在此，我们发现27 HC引起细胞ROS的积累，其上调基质金属蛋白酶9（MMP 9）并增加MCF 7和T47 D细胞的侵袭能力。27 HC以时间和剂量依赖性方式降低MCF 7和T47 D细胞中具有Kazal基序的逆转诱导富含半胱氨酸蛋白（RECK）的蛋白和mRNA水平。在MCF 7细胞中，27 HC通过ROS诱导DNA甲基化介导RECK下调。RECK基因敲低可增加MCF 7细胞MMP 9的活性和mRNA水平，促进MCF 7细胞的侵袭。我们还发现RECK敲低上调MCF 7细胞中p-STAT-3的水平。此外，RECK的过表达减弱了MCF 7细胞中27 HC诱导的侵袭。RECK过表达也抑制27 HC诱导的p-STAT-3上调。总的来说，结果表明，27 HC通过ROS诱导的DNA甲基化下调RECK，从而激活STAT-3信号通路。RECK可作为介导27 HC对乳腺癌作用的新靶点。
Abstract Breast cancer is an important and common tumour among women worldwide. We previously showed that 27-hydroxycholesterol (27HC) promoted the invasion and migration of breast cancer cells and activated signal transducer and activator of transcription 3 (STAT-3) signalling through reactive oxygen species (ROS). However, the regulation of STAT-3 signalling by ROS needs to be further explored. Here, we showed that 27HC caused the accumulation of cellular ROS, which upregulated matrix metalloproteinase 9 (MMP9) and increased the invasive ability of MCF7 and T47D cells. 27HC decreased the protein and mRNA levels of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) in a time- and dose-dependent manner in MCF7 and T47D cells. RECK downregulation was mediated by 27HC-induced DNA methylation via ROS in MCF7 cells. RECK knockdown increased the activity and mRNA levels of MMP9, and promoted the invasion of MCF7 cells. We also found RECK knockdown upregulated the level of p-STAT-3 in MCF7 cells. Furthermore, overexpression of RECK attenuated 27HC-induced invasion in MCF7 cells. RECK overexpression also inhibited p-STAT-3 upregulation induced by 27HC. Collectively, the results showed that DNA methylation induced by 27HC via ROS downregulated RECK, thereby activating the STAT-3 signalling pathway. RECK could serve as a novel target mediating the effect of 27HC on breast cancer.