HB-EGF upregulates StAR expression and stimulates progesterone production through ERK1/2 signaling in human granulosa-lutein cells

Abstract

Background Heparin-binding epidermal growth factor-like growth factor (HB-EGF) belongs to the epidermal growth factor (EGF) family of growth factors. HB-EGF and its receptors, epidermal growth factor receptor (EGFR) and HER4, are expressed in the human corpus luteum. HB-EGF has been shown to regulate luteal function by preventing cell apoptosis. Steroidogenesis is the primary function of the human corpus luteum. Steroidogenic acute regulatory protein (StAR) plays a critical role in steroidogenesis. StAR expression and progesterone (P4) production in human granulosa-lutein (hGL) cells have been shown to be upregulated by a ligand of EGFR, amphiregulin. However, whether HB-EGF can achieve the same effects remains unknown. Methods A steroidogenic human ovarian granulosa-like tumor cell line, KGN, and primary culture of hGL cells obtained from patients undergoing in vitro fertilization treatment were used as experimental models. The underlying molecular mechanisms mediating the effects of HB-EGF on StAR expression and P4 production were explored by a series of in vitro experiments. Results Western blot showed that EGFR, HER2, and HER4 were expressed in both KGN and hGL cells. Treatment with HB-EGF for 24 h induced StAR expression but did not affect the expression of steroidogenesis-related enzymes, P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase, and aromatase. Using pharmacological inhibitors and a siRNA-mediated knockdown approach, we showed that EGFR, HER4, but not HER2, were required for HB-EGF-stimulated StAR expression and P4 production. In addition, HB-EGF-induced upregulations of StAR expression and P4 production were mediated by the activation of the ERK1/2 signaling pathway. Conclusion This study increases the understanding of the physiological role of HB-EGF in human luteal functions.

Resveratrol stimulates StAR expression and progesterone production by GPER-mediated downregulation of Snail expression in human granulosa cells

“…As shown in Fig. 4C and D , due to the off-target effect, pretreatment with U0126 increased the basal protein levels of StAR, which is consistent with our previous study [ 26 ]. However, inhibition of ERK1/2 signaling blocked the RSV-induced upregulation of StAR protein levels in both KGN and primary hGL cells.…”

“…HB-EGF then binds and activates EGFR leading to downstream activation of signaling molecules, such as ERK1/2 [ 35 , 36 ]. Our recent study demonstrates that HB-EGF induces upregulation of StAR expression and P4 production in both KGN and primary hGL cells and these effects require the EGFR-mediated activation of the ERK1/2 signaling pathway [ 26 ]. In the present study, our results showed that activation of ERK1/2 signaling was involved in RSV-stimulated StAR expression and P4 production in both KGN and primary hGL cells.…”

Signaling pathways and targeted therapeutic strategies for polycystic ovary syndrome

“…However, other studies have revealed inhibition of the ERK pathway and reduced HB-EGF levels in PCOS patients (188). Expression of StAR and subsequently increased progesterone synthesis could be modulated by upregulation of ERK activity (189,190). A series of studies have demonstrated that administration of an NK3R antagonist (fezolinetant) leads to a reduction in LH secretion and attenuates symptoms of PCOS by reducing GnRH pulse generation (191).…”

Resveratrol Protects Rat Ovarian Luteinized Granulosa Cells from H2O2-Induced Dysfunction by Activating Autophagy

“…The evolution of the corpus luteum includes development, maintenance, and degradation, which are essential for maintaining a normal menstrual cycle, regulating the development of follicles, promoting the implantation of embryos, and protecting the safety of early pregnancy [ 3 , 4 ]. Dysfunction of the corpus luteum is involved in some diseases of the corpus luteum such as corpus luteum rupture and luteal phase deficiency [ 5 , 6 ].…”