Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry
Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry
复制标题
ACE2/Ang-(1-7)/Mas轴的下调通过增强钙库操作的钙进入促进乳腺癌转移
DOI：
10.1016/j.canlet.2016.04.006
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发表时间：
2016-07-01
期刊：
影响因子：
9.7
通讯作者：
Zou, Fei
中科院分区：
文献类型：
--
作者：
Yu, Changhui;Tang, Wei;Zou, Fei
肾素-血管紧张素系统（renin-angiotensin system， RAS）是肿瘤微环境的重要组成部分，在促进癌细胞增殖、血管生成、代谢、迁移和侵袭等方面发挥着关键作用。同时，与RAS相关的血管紧张素转换酶（ACE）2/血管紧张素-(1-7)[Ang-(1-7)]/Mas轴臂具有抗增殖、血管舒张和抗转移特性。先前的研究表明，Ang-(1-7)通过抑制癌症相关成纤维细胞来减少原位人乳腺肿瘤的增殖。然而，ACE/Ang-(1-7)/Mas轴在乳腺癌细胞转移中的作用尚不清楚。在本研究中，我们发现ACE2蛋白水平与乳腺癌细胞转移能力和乳腺肿瘤分级呈负相关。上调ACE2/Ang-(1-7)/Mas轴在体内外抑制乳腺癌细胞的迁移和侵袭。在机制上，ACE2/Ang-(1-7)/Mas轴激活抑制储存操作钙进入（SOCE）和PAK1/NF-kappa B/Snail1通路，诱导E-cadherin表达。综上所述，我们的研究结果表明，ACE2/Ang-(1-7)/Mas轴的下调通过激活SOCE和PAK1/NF-kappa B/Snail1途径刺激乳腺癌转移。这些结果为乳腺癌发生转移提供了新的机制，并为通过调节ACE2/Ang-(1-7)/Mas轴开发新的抗转移治疗转移性乳腺癌提供了思路。2016爱思唯尔爱尔兰有限公司版权所有。
The renin-angiotensin system (RAS) is an important component of the tumor microenvironment and plays a key role in promoting cancer cell proliferation, angiogenesis, metabolism, migration and invasion. Meanwhile, the arm of angiotensin-converting enzyme (ACE)2/angiotensin-(1-7) [Ang-(1-7)]/Mas axis in connection with RAS is associated with anti-proliferative, vasodilatory and anti-metastatic properties. Previous studies have shown that Ang-(1-7) reduces the proliferation of orthotopic human breast tumor growth by inhibiting cancer-associated fibroblasts. However, the role of ACE/Ang-(1-7)/Mas axis in the metastasis of breast cancer cells is still unknown. In the present study, we found that ACE2 protein level is negatively correlated with the metastatic ability of breast cancer cells and breast tumor grade. Upregulation of ACE2/Ang-(1-7)/Mas axis inhibits breast cancer cell migration and invasion in vivo and in vitro. Mechanistically, ACE2/Ang-(1-7)/Mas axis activation inhibits store-operated calcium entry (SOCE) and PAK1/NF-kappa B/Snail1 pathways, and induces E-cadherin expression. In summary, our results demonstrate that downregulation of ACE2/Ang-(1-7)/Mas axis stimulates breast cancer metastasis through the activation of SOCE and PAK1/NF-kappa B/Snail1 pathways. These results provide new mechanisms by which breast cancer develop metastasis and shed light on developing novel anti-metastasis therapeutics for metastatic breast cancer by modulating ACE2/Ang-(1-7)/Mas axis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.