Vasohibin 2 promotes epithelial-mesenchymal transition in human breast cancer via activation of transforming growth factor β 1 and hypoxia dependent repression of GATA-binding factor 3
Vasohibin 2 promotes epithelial-mesenchymal transition in human breast cancer via activation of transforming growth factor β 1 and hypoxia dependent repression of GATA-binding factor 3
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Vasohibin 2 通过激活转化生长因子 β 1 和缺氧依赖性抑制 GATA 结合因子 3 促进人乳腺癌上皮间质转化
DOI：
10.1016/j.canlet.2016.11.016
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发表时间：
2017-03-01
期刊：
影响因子：
9.7
通讯作者：
Miao, Yi
中科院分区：
文献类型：
--
作者：
Tu, Min;Li, Zhanjun;Miao, Yi
Vasohibin 2（VASH 2）是一种血管生成因子，与肿瘤血管生成、增殖和上皮-间质转化（EMT）有关。为了研究VASH 2在乳腺癌中的EMT作用，我们在人乳腺癌细胞系中过表达或敲低VASH 2的表达。我们观察到VASH 2在体外和体内诱导EMT。转化生长因子β 1（TGF β 1）通路被VASH 2激活，显性负性TGF β II型受体的表达可以阻断VASH 2介导的EMT。在临床乳腺癌组织中，VASH 2与TGF β 1表达呈正相关，而与EMT标志物E-cadherin表达呈负相关。在体外或体内缺氧条件下，我们发现在VASH 2过表达的ESR 1阳性细胞中，雌激素受体1（ESR 1）的下调抑制了E-钙粘蛋白。相关系数分析显示，临床乳腺癌组织中VASH 2和ESR 1的表达呈负相关。进一步的研究表明，在缺氧或体内，ESR 1的转录因子GATA结合因子3（GATA 3）被VASH 2下调。这些发现表明，VASH 2通过激活TGF β 1途径和缺氧依赖性抑制GATA 3-ESR 1途径驱动乳腺癌细胞经历EMT，导致癌症转移。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Vasohibin 2 (VASH2) is identified as an angiogenic factor, and has been implicated in tumor angiogenesis, proliferation and epithelial-mesenchymal transition (EMT). To investigate the EMT role of VASH2 in breast cancer, we overexpressed or knocked down expression of VASH2 in human breast cancer cell lines. We observed that VASH2 induced EMT in vitro and in vivo. The transforming growth factor beta 1 (TGF beta 1) pathway was activated by VASH2, and expression of a dominant negative TGF beta type II receptor could block VASH2-mediated EMT. In clinical breast cancer tissues VASH2 positively correlated with TGF beta 1 expression, but negatively correlated with E-cadherin (a marker of EMT) expression. Under hypoxic conditions in vitro or in vivo, we found that down-regulation of estrogen receptor 1 (ESR1) in VASH2 overexpressing ESR1 positive cells suppressed E-cadherin. Correlation coefficient analysis indicated that VASH2 and ESR1 expression were negatively correlated in clinical human breast cancer tissues. Further study revealed that a transcription factor of ESR1, GATA-binding factor 3 (GATA3), was down-regulated by VASH2 under hypoxia or in vivo. These findings suggest that VASH2 drives breast cancer cells to undergo EMT by activation of the TGF beta 1 pathway and hypoxia dependent repression GATA3-ESR1 pathway, leading to cancer metastasis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.