Abstract
Sprouty2 (SPRY2) is an important intracellular regulator for epidermal growth factor receptor (EGFR)-mediated ERK1/2 signaling. In human granulosa cells, although SPRY2 is expressed, its regulation and function remains complete unknown and must be defined. Our previous study has shown that human chorionic gonadotropin (hCG)/luteinizing hormone (LH) up-regulates the expression levels of EGF-like growth factor, amphiregulin (AREG), which subsequently contributes to the hCG/LH-induced COX-2 expression and PGE2 production. The aim of the present study was to investigate the effect of hCG on SPRY2 expression and the role of hCG-induced SPRY2 in AREG-stimulated COX-2 expression and PGE2 production in human granulosa cells. Our results demonstrated that the expression of SPRY2 was up-regulated by hCG treatment. Using pharmacological inhibitors and siRNA knockdown, we showed that activation of ERK1/2 signaling was required for hCG-induced up-regulation of SPRY2 expression. Further, SPRY2 knockdown attenuated the AREG-induced COX-2 expression and PGE2 production by inhibiting AREG-activated ERK1/2 signaling. Interestingly, we showed that SPRY2 expression levels were significantly increased in granulosa cells of ovarian hyperstimulation syndrome (OHSS) patients. These results for the first time elucidate the physiological roles of SPRY2 in human granulosa cells and suggest that aberrant expression of SPRY2 may contribute to the pathogenesis of OHSS.
Highlights
Sprouty (SPRY) was first identified in Drosophila, where it acts as an antagonistic regulator of tracheal branching[1]
Our results showed that treatment with human chorionic gonadotropin (hCG) up-regulated SPRY2 expression in human granulosa cells through activation of the ERK1/2 signaling pathway
It has been shown that EGF, fibroblast growth factor (FGF) or platelet-derived growth factor (PDGF) up-regulates SPRY2 expression by activating the ERK1/2 signaling pathway[19]
Summary
Sprouty (SPRY) was first identified in Drosophila, where it acts as an antagonistic regulator of tracheal branching[1]. Our previous study shows that LH up-regulates the expression levels of AREG, BTC and EREG, which subsequently contribute to the LH-induced COX-2 expression and PGE2 production in human granulosa cells[15]. Taken together, these studies indicate that LH and LH-induced EGF-like growth factors play critical roles in the regulation of ovulation. If LH/hCG treatment does up-regulate SPRY2 expression, whether SPRY2 mediates EGF-like growth factor-induced COX-2 expression and PGE2 production in human granulosa cells remains unknown. We found that the expression levels of SPRY2 were significantly higher in the granulosa cells of ovarian follicles from IVF patients who later developed ovarian hyperstimulation syndrome (OHSS)
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