title: Glucocorticoid receptor-mediated insulin-like growth factor-I transcriptional regulation in BeWo trophoblast cells before and after syncytialisation.
abstract: 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.
authors: Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing 210095, PR China.
authors: Bin
authors: B
authors: He
authors: Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing 210095, PR China.
authors: Nana
authors: N
authors: Zhang
authors: Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing 210095, PR China.
authors: Yimin
authors: Y
authors: Jia
authors: Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing 210095, PR China.
authors: Qinwei
authors: Q
authors: Sun
authors: Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing 210095, PR China; Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control, Nanjing 210095, PR China. Electronic address: zhao.ruqian@gmail.com.
authors: Ruqian
authors: R
authors: Zhao
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003907:Dexamethasone / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011863:Radioimmunoassay; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D027283:Large Neutral Amino Acid-Transporter 1; D011965:Receptors, Glucocorticoid; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone
keywords: Cytotrophoblast; Dexamethasone; Insulin-like growth factor-I; Placenta; Syncytiotrophoblast