Vasohibin 2 promotes human luminal breast cancer angiogenesis in a non-paracrine manner via transcriptional activation of fibroblast growth factor 2
Vasohibin 2 promotes human luminal breast cancer angiogenesis in a non-paracrine manner via transcriptional activation of fibroblast growth factor 2
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Vasohibin 2 通过成纤维细胞生长因子 2 的转录激活以非旁分泌方式促进人管腔乳腺癌血管生成
DOI：
10.1016/j.canlet.2016.09.031
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发表时间：
2016-12-28
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;Lu, Cheng;Miao, Yi
Vasohibin 2（VASH2）是一种血管生成因子和癌症相关蛋白，通过旁分泌机制发挥作用。在这里，我们研究了血管生成功能和作用机制的VASH2在200人乳腺癌组织进行免疫组化染色，蛋白质印迹，间接夹心酶联免疫吸附试验（ELISA），和半定量的基于抗体阵列。建立稳定过表达VASH2或具有敲低的VASH2的乳腺癌细胞，并用于体内和体外模型。在人管腔组织中，而不是在HER2阳性或基底样乳腺癌组织中，VASH2与CD31阳性微血管密度呈正相关，诱导异种移植肿瘤中的血管生成，并促进体外人脐静脉内皮细胞管形成。从敲低VASH2和VASH2过表达的管腔型乳腺癌细胞收集的浓缩条件培养基中不存在VASH2表达。此外，VASH2调节人管腔型乳腺癌细胞中成纤维细胞生长因子2（FGF2）的表达，并且VASH2过表达诱导的促血管生成作用在体外被FGF2中和阻断。此外，双荧光素酶报告基因分析和染色质免疫沉淀分析结果表明，FGF2启动子通过组蛋白修饰被VASH2转录激活。总之，VASH2表达与FGF2表达呈正相关，并通过非旁分泌机制转录激活成纤维细胞生长因子2促进人管腔型乳腺癌中的血管生成。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Vasohibin 2 (VASH2) is an angiogenic factor and cancer-related protein that acts via paracrine mechanisms. Here, we investigated the angiogenic function and mechanism of action of VASH2 in 200 human breast cancer tissues by performing immunohistochemical staining, western blot, indirect sandwich enzyme-linked immunosorbent assay (ELISA), and a semi-quantitative sandwich-based antibody array. Breast cancer cells stably overexpressing VASH2 or with knocked-down VASH2 were established and used for in vivo and in vitro models. In human luminal tissue, but not in HER2-positive or basal-like breast cancer tissues, VASH2 was positively correlated with CD31-positive microvascular density, induced angiogenesis in xenograft tumors, and promoted human umbilical vein endothelial cell tube formation in vitro. VASH2 expression was absent in the concentrated conditioned medium collected from knocked down VASH2 and VASH2-overexpressing luminal breast cancer cells. Further, VASH2 regulated the expression of fibroblast growth factor 2 (FGF2) in human luminal breast cancer cells, and the proangiogenic effect induced by VASH2 overexpression was blocked by FGF2 neutralization in vitro. Additionally, dual luciferase reporter assay and Chromatin immunoprecipitation analysis results showed that FGF2 promoter was transcriptionally activated by VASH2 via histone modifications. In conclusion, VASH2 expression is positively correlated with FGF2 expression and promotes angiogenesis in human luminal breast cancer by transcriptional activation of fibroblast growth factor 2 through non-paracrine mechanisms. (C) 2016 Elsevier Ireland Ltd. All rights reserved.