title: hCG-induced Sprouty2 mediates amphiregulin-stimulated COX-2/PGE2 up-regulation in human granulosa cells: a potential mechanism for the OHSS.
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.
authors.affiliation: Department of Obstetrics and Gynaecology, Child &Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
authors.forename: Jung-Chien
authors.initials: JC
authors.lastname: Cheng
authors.affiliation: Department of Obstetrics and Gynaecology, Child &Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.|Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Obstetrics and Gynaecology, Child &Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
authors.forename: Hsun-Ming
authors.initials: HM
authors.lastname: Chang
authors.affiliation: Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Ying-Pu
authors.initials: YP
authors.lastname: Sun
authors.affiliation: Department of Obstetrics and Gynaecology, Child &Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006107:Granulosa Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007986:Luteinizing Hormone / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008565:Membrane Proteins / Q000096:biosynthesis*; D016471:Ovarian Hyperstimulation Syndrome / Q000378:metabolism* / Q000473:pathology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C485561:SPRY2 protein, human; D007986:Luteinizing Hormone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone