Activation of G protein-coupled estrogen receptor stimulates placental human chorionic gonadotropin expression through PKA-CREB signaling

The placenta-secreted human chorionic gonadotropin (hCG) is a hormone that plays a critical role in inducing ovarian progesterone production, which is required for maintaining normal pregnancy. The bioavailability of hCG depends on the expression of the beta-subunit of hCG (hCG-β) which is encoded by the chorionic gonadotropin beta (CGB) gene. G protein-coupled estrogen receptor (GPER) is a membrane estrogen receptor involved in non-genomic estrogen signaling. Estradiol (E2) has been shown to stimulate hCG production. However, the role of the GPER in regulating CGB expression remains unknown. In the present study, our results revealed that treatment with G1 upregulated CGB expression in two human choriocarcinoma cell lines, BeWo and JEG-3, and primary human cytotrophoblast cells. In addition, G1 treatment activated the cAMP-response element binding protein (CREB). Using a pharmacological inhibitor and siRNA-mediated knockdown approach, we showed that the stimulatory effect of G1 on CGB expression is mediated by the protein kinase A (PKA)-CREB signaling pathway. This study increases the understanding of the role of GPER in the human placenta. In addition, our results provide important insights into the molecular mechanisms that mediate hCG expression, which may lead to the development of alternative therapeutic approaches for treating placental diseases.