Estradiol-induced vascular endothelial growth factor-A expression in breast tumor cells is biphasic and regulated by estrogen receptor-alpha dependent pathway.
Estradiol-induced vascular endothelial growth factor-A expression in breast tumor cells is biphasic and regulated by estrogen receptor-alpha dependent pathway.
复制标题
DOI：
10.3892/ijo.22.3.609
复制
发表时间：
2003-03
影响因子：
5.2
通讯作者：
K. Sengupta;S. Banerjee;N. Saxena;S. Banerjee
中科院分区：
文献类型：
--
作者：
K. Sengupta;S. Banerjee;N. Saxena;S. Banerjee
雌激素具有调节血管内皮生长因子-A(VEGF-A)的生理和病理生理功能。然而，雌激素对血管内皮细胞生长因子-A基因表达的影响尚未完全阐明。我们发现，在ER+MCF-7乳腺肿瘤细胞中，17β-雌二醇(17β-E_2)诱导的血管内皮生长因子-A mRNA转录激活有两个阶段，一个是早期反应，一个是晚期反应，这取决于暴露时间的长短。17β-E_2作用2小时后，肿瘤细胞中的血管内皮生长因子-A基因表达水平显著高于对照组。此外，环己酰亚胺不能抑制这种诱导，表明这是雌激素的直接作用。17β-E_2作用6h后，MCF-7细胞中VEGF-AmRNA的表达恢复到基础水平，但在作用24 h后，其表达水平又显著增强，而放线菌酮不能改变这种诱导作用，这表明从头合成蛋白不是必需的，与早期反应一样，这是雌激素的直接作用。抗雌激素ICI182,780是早期反应阶段的纯拮抗剂，但对晚期反应阶段有部分但显著的影响，进一步表明早期和晚期都是ER依赖的。在缺乏雌激素受体(ER-α)的人乳腺上皮细胞(HMEC)中，未发现17β-E_2对VEGF-A基因表达的早期和晚期诱导作用，而17β-E_2作用于HMEC 2或24小时后，在早期和晚期均可观察到明显的诱导作用。这些研究表明，VEGF-A是一个雌激素反应基因，雌激素对该基因表达的调控是双向的，并可通过ER-α途径介导。
Estrogens have been shown to regulate vascular endothelial growth factor-A (VEGF-A) for physiological and patho-physiological functions. However, estrogen action on VEGF-A mRNA expression has not been completely elucidated. We have identified two phases of activation of VEGF-A mRNA transcription, one early and one late response, induced by 17beta-estradiol (17beta-E2) in ER+ MCF-7 breast tumor cells, depending upon the length of exposure. VEGF-A mRNA level was significantly higher than control in tumor cells after 2 h of 17beta-E2 exposure. Furthermore this induction was not inhibited by cycloheximide, indicating that it was a direct effect of estrogen. In contrast VEGF-A mRNA expression was back at basal level in MCF-7 cells exposed to 17beta-E2 for 6 h. However, expression levels were again significantly augmented after 24 h of exposure, and this induction was unaltered by cycloheximide indicating that de novo protein synthesis was not required and like early response, it was a direct effect of estrogen. The antiestrogen ICI 182,780 was a pure antagonist for the early response phase of VEGF-A mRNA induction, but it had partial but significant effect on the late response phase, further suggesting that both early and late phases were ER dependent. In human mammary epithelial cells (HMEC) lacking estrogen receptor (ER-alpha) the early and late response phase of VEGF-A mRNA induction in response to 17beta-E2 was not found, but significant inductions were seen in the early and late phases when ER-alpha transfected HMEC were exposed to 17beta-E2 for 2 or 24 h. Taken together, these studies suggest that VEGF-A is an estrogen responsive gene and modulation of this gene expression by estrogen is biphasic and can be mediated through ER-alpha dependent pathway.