ZEB1 Upregulates VEGF Expression and Stimulates Angiogenesis in Breast Cancer.
ZEB1 Upregulates VEGF Expression and Stimulates Angiogenesis in Breast Cancer.
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ZEB1 上调乳腺癌中 VEGF 表达并刺激血管生成
DOI：
10.1371/journal.pone.0148774
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yang S
中科院分区：
文献类型：
--
作者：
Liu L;Tong Q;Liu S;Cui J;Zhang Q;Sun W;Yang S
虽然锌指E-box结合同源框1（ZEB 1）已被确定为调节乳腺癌分化和转移的关键因子，但其在调节肿瘤血管生成中的潜在作用尚未得到充分研究。在这里，我们提出了新的发现，条件培养基来自ZEB 1表达MDA-MB-231细胞显着增加人脐静脉内皮细胞（HUVEC）的毛细血管形成，而ZEB 1敲低RNA干扰有相反的效果。ZEB 1引起血管内皮生长因子A（VEGFA）在mRNA和蛋白水平的表达显着上调。HUVEC与抗VEGFA中和抗体的预孵育减弱了ZEB 1介导的HUVEC管形成。乳腺癌组织中ZEB 1的表达与VEGFA、CD 31的表达呈正相关。在分子水平上，ZEB 1通过增加SP1向其启动子的募集来激活VEGFA转录，这是通过激活PI 3 K和p38途径介导的。使用裸鼠异种移植模型，我们证明了ZEB 1的表达升高促进乳腺癌的体内肿瘤发生和血管生成。总的来说，我们发现表达ZEB 1的乳腺癌细胞增加VEGFA的产生，从而通过旁分泌机制刺激肿瘤生长和血管生成。
Although zinc finger E-box binding homeobox 1 (ZEB1) has been identified as a key factor in the regulation of breast cancer differentiation and metastasis, its potential role in modulating tumor angiogenesis has not been fully examined. Here, we present the novel finding that conditioned medium derived from ZEB1-expressing MDA-MB-231 cells significantly increased the capillary tube formation of human umbilical vein endothelial cells (HUVECs), whereas ZEB1 knockdown by RNA interference had the opposite effect. ZEB1 caused marked upregulation of the expression of vascular endothelial growth factor A (VEGFA) at both mRNA and protein levels. Pre-incubation of HUVECs with anti-VEGFA neutralized antibody attenuated ZEB1-mediated tube formation of HUVECs. In breast cancer tissues, expression of ZEB1 was positively correlated with those of VEGFA and CD31. At the molecular level, ZEB1 activated VEGFA transcription by increasing SP1 recruitment to its promoter, which was mediated via the activation of PI3K and p38 pathways. Using a nude mouse xenograft model, we demonstrated that elevated expression of ZEB1 promotes in vivo tumorigenesis and angiogenesis in breast cancer. Collectively, we found that ZEB1-expressing breast cancer cells increase VEGFA production and thus stimulate tumor growth and angiogenesis via a paracrine mechanism.