Abstract
Progesterone plays critical roles in maintaining a successful pregnancy at the early embryonic stage. Human chorionic gonadotropin (hCG) rapidly induces amphiregulin (AREG) expression. However, it remains unknown whether AREG mediates hCG-induced progesterone production. Thus, the objective of this study was to investigate the role of AREG in hCG-induced progesterone production and the underlying molecular mechanism in human granulosa cells; primary cells were used as the experimental model. We demonstrated that the inhibition of EGFR and the knockdown of AREG abolished hCG-induced steroidogenic acute regulatory protein (StAR) expression and progesterone production. Importantly, follicular fluid AREG levels were positively correlated with progesterone levels in the follicular fluid and serum. Treatment with AREG increased StAR expression and progesterone production, and these stimulatory effects were abolished by EGFR inhibition. Moreover, activation of ERK1/2, but not PI3K/Akt, signaling was required for the AREG-induced up-regulation of StAR expression and progesterone production. Our results demonstrate that AREG mediates hCG-induced StAR expression and progesterone production in human granulosa cells, providing novel evidence for the role of AREG in the regulation of steroidogenesis.
Highlights
After ovulation, luteinizing hormone (LH) stimulates granulosa cells to produce progesterone[1,2]
We demonstrate for the first time that AREG mediates human chorionic gonadotropin (hCG)-induced steroidogenic acute regulatory protein (StAR) expression and progesterone expression in human granulosa cells
Our results demonstrate that the Epidermal growth factor receptor (EGFR)-mediated activation of ERK1/2 signaling is required for AREG-induced StAR expression and progesterone production in human granulosa cells
Summary
After ovulation, luteinizing hormone (LH) stimulates granulosa cells to produce progesterone[1,2]. Expression in mouse follicles[14] These results suggest that AREG, BTC and EREG play important roles in mediating the biological functions of LH/hCG in granulosa cells. AREG is thought to be the most abundant EGFR ligand in human follicular fluid It remains unknown whether AREG mediates LH/ hCG-induced StAR expression and progesterone production in human granulosa cells. We tested the hypothesis that AREG mediates the hCG-induced up-regulation of StAR expression and progesterone production in human granulosa cells. We found that inhibition of EGFR activity and knockdown of AREG attenuated the hCG-induced up-regulation of StAR expression and progesterone production. Using pharmacological inhibitors and specific siRNA, our results further demonstrated that AREG up-regulated StAR expression and progesterone expression via EGFR-mediated activation of the ERK1/2 signaling pathway in human granulosa cells
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