Amphiregulin stimulates human chorionic gonadotropin expression by inducing ERK1/2-mediated ID3 expression in trophoblast cells

Abstract

Introduction: The human chorionic gonadotropin (hCG) is a dimer consisting of an α subunit and a β subunit which is encoded by the CGB gene and is unique to hCG. hCG is a hormone mainly synthesized by syncytiotrophoblast cells in the placenta, plays a critical role in stimulating progesterone production that is necessary for maintaining normal pregnancy in the early stage. Epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinase family which has been shown to regulate various physiological and pathological events. In human chorionic villi and amniotic fluid, amphiregulin (AREG) is reported to be the most abundant EGFR ligand and can stimulate hCG expression. However, the underlying mechanism remains unknown.

Methods: We use BeWo cells, the commonly used cell model for the hCG production of trophoblast cells, as an in vitro model. The effects of AREG on CGB expression and hCG secretion as well as the underlying mechanisms were explored by a series of in vitro experiments.

Results: We show that treatment with AREG stimulates CGB expression and hCG secretion. Using pharmacological inhibitors, we show that the stimulatory effects of AREG on CGB expression and hCG secretion are mediated by the EGFR-activated ERK1/2 signaling pathways. In addition, the expression of inhibitor of DNA-binding protein 3 (ID3) is upregulated by AREG. Knockdown of ID3 attenuates the AREG-induced upregulation of CGB expression and hCG secretion.

Discussion: This study provides important insights into the molecular mechanisms that mediate AREG-induced upregulation of hCG production in human trophoblast cells which may lead to the development of alternative therapeutic approaches for the treatment of placental diseases.

Keywords: AREG; ID3; Trophoblast cells; hCG.