Glucocorticoid receptor-mediated insulin-like growth factor-I transcriptional regulation in BeWo trophoblast cells before and after syncytialisation
Glucocorticoid receptor-mediated insulin-like growth factor-I transcriptional regulation in BeWo trophoblast cells before and after syncytialisation
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BeWo滋养层细胞合胞化前后糖皮质激素受体介导的胰岛素样生长因子-I转录调控
DOI：
10.1016/j.steroids.2016.08.004
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发表时间：
2016-11-01
期刊：
影响因子：
2.7
通讯作者：
Zhao, Ruqian
中科院分区：
文献类型：
--
作者：
He, Bin;Zhang, Nana;Zhao, Ruqian
产前暴露于过量的糖皮质激素（GCs）导致宫内生长迟缓和胎儿编程的成人健康和疾病通过解除胎盘功能。胎盘分泌胰岛素样生长因子- i （IGF-I）在调节胎盘发育和功能中起关键作用。然而，GCs是否通过糖皮质激素受体（glucocorticoid receptor， GR）介导的igf - 1基因的转录调控影响胎盘功能仍不清楚。本研究以人胎盘绒毛膜癌（BeWo）细胞合胞前和合胞后分别作为细胞滋养层细胞和合胞滋养层细胞模型，探讨地塞米松（Dex）对两个阶段IGF-I基因转录调控的影响。Dex显著抑制细胞滋养层细胞增殖（P < 0.05），下调合胞滋养层细胞氨基酸转运蛋白SLC7A5的表达。同时，IGF-I mRNA及其转录变体的丰度和培养基中IGF-I水平显著降低，与GR磷酸化显著增强（P < 0.05）相关。GR拮抗剂RU486能够消除所有这些影响。在IGF-I基因的启动子区域预测了两个糖皮质激素反应元件（GREs）。Dex处理后，GR与GRE1的结合在细胞滋养细胞和合细胞滋养细胞中均显著增强（P < 0.05），而与GRE2的结合在细胞滋养细胞中显著减弱（P < 0.05），而在合细胞滋养细胞中无明显减弱。补充igf - 1完全恢复了dex诱导的细胞周期阻滞，但不能抑制SLC7A5的下调，表明不同的调节机制。综上所述，我们的研究结果表明gr介导的IGF-I转录调控参与了dex诱导的胎盘细胞增殖和功能的抑制。(C) 2016 Elsevier Inc.版权所有。
Prenatal exposure to excessive glucocorticoids (GCs) leads to intrauterine growth retardation and fetal programming of adult health and disease through deregulation of placental functions. Placental secretion of insulin-like growth factor-I (IGF-I) plays a critical role in the regulation of placental development and function. However, it remains elusive whether GCs affect placental functions through glucocorticoid receptor (GR)-mediated transcriptional regulation of IGF-I gene. In this study, human placental choriocarcinoma (BeWo) cells before and after syncytialization were used as cytotrophoblast and syncytiotrophoblast models, respectively, to explore the effects of dexamethasone (Dex) on transcriptional regulation of IGF-I gene at both stages. Dex significantly inhibited (P < 0.05) cell proliferation in cytotrophoblasts and down-regulated amino acid transporter SLC7A5 in syncytiotrophoblasts. Concurrently, the abundance of IGF-I mRNA and its transcript variants, together with IGF-I level in culture media, were significantly reduced, in association with significantly enhanced (P < 0.05) GR phosphorylation. GR antagonist RU486 was able to abolish all these effects. Two glucocorticoid response elements (GREs) were predicted in the promoter regions of IGF-I gene. GR binding to GRE1 was significantly enriched (P < 0.05) in both cytotrophoblasts and syncytiotrophoblasts, but that to GRE2 was significantly diminished (P < 0.05) in cytotrophoblasts but not in syncytiotrophoblasts, in response to Dex treatment. IGF-I supplementation completely rescued Dex-induced cell cycle arrest but not SLC7A5 down-regulation, indicating different regulatory mechanisms. Taken together, our results suggest that GR-mediated transcriptional regulation of IGF-I is involved in Dex-induced inhibition of placental cell proliferation and function. (C) 2016 Elsevier Inc. All rights reserved.