Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition.
Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition.
复制标题
铜消耗通过下调 HIF-1 和抑制 Snail/Twist 介导的上皮间质转化来抑制 CoCl2 诱导的 MCF-7 细胞的侵袭性表型
DOI：
10.1038/srep12410
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发表时间：
2015-07-15
影响因子：
4.6
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Li S;Zhang J;Yang H;Wu C;Dang X;Liu Y
铜是一种受到严格调控的微量元素，对包括血管生成在内的许多生理过程都是必需的。血管生成失调与肿瘤中铜的增加有关，因此铜螯合剂已用于抑制肿瘤血管生成。然而，目前尚不清楚铜是否对上皮间质转化（EMT）有任何影响。利用CoCl 2诱导的人乳腺癌MCF-7细胞EMT，我们发现TEPA，一种铜螯合剂，抑制CoCl 2引发的EMT样细胞形态和细胞骨架排列;降低波形蛋白和纤连蛋白的表达，EMT的典型标志物;抑制HIF-1激活和HIF 1-α在核中的积聚;并下调缺氧相关转录因子Snail和Twist 1的表达。此外，敲低铜转运蛋白，Ctr 1，也抑制氯化钴诱导的EMT和逆转间充质表型。在EMT 6异种移植小鼠模型中，TEPA施用抑制肿瘤生长并增加小鼠存活。异种移植物的免疫组织化学分析进一步表明，TEPA管理显着抑制肿瘤血管生成，下调缺氧诱导的转录因子，蜗牛和Twist 1，导致EMT相关的标记基因，波形蛋白和纤连蛋白的反式激活减少。这些结果表明，TEPA抑制CoCl 2诱导的EMT最有可能通过HIF 1-α-Snail/Twist信号通路，铜耗竭可用作乳腺癌的治疗。
Copper, a strictly regulated trace element, is essential for many physiological processes including angiogenesis. Dysregulated angiogenesis has been associated with increased copper in tumors and thus copper chelators have been used to inhibit tumor angiogenesis. However, it remains unclear whether copper has any effect on epithelial-mesenchymal transition (EMT). Using CoCl2-induced EMT of human breast carcinoma MCF-7 cells, we found that TEPA, a copper chelator, inhibited EMT-like cell morphology and cytoskeleton arrangement triggered by CoCl2; decreased the expression of vimentin and fibronectin, markers typical of EMT; inhibited HIF-1 activation and HIF1-α accumulation in nuclear; and down-regulated the expression of hypoxia-associated transcription factors, Snail and Twist1. Moreover, knockdown copper transport protein,Ctr1, also inhibited CoCl2-induced EMT and reversed the mesenchymal phenotype. In EMT6 xenograft mouse models, TEPA administration inhibited the tumor growth and increased mice survival. Immunohistochemical analysis of the xenograft further demonstrated that TEPA administration significantly inhibited tumor angiogenesis, down-regulated hypoxia-induced transcription factors, Snail and Twist1, leading to decreased transactivation of EMT-associated marker genes, vimentin and fibronectin. These results indicate that TEPA inhibits CoCl2-induced EMT most likely via HIF1-α-Snail/Twist signaling pathway and copper depletion may be exploited as a therapeutic for breast cancer.