title: Defective CFTR-regulated granulosa cell proliferation in polycystic ovarian syndrome.
abstract: Polycystic ovarian syndrome (PCOS) is one of the most frequent causes of female infertility, featured by abnormal hormone profile, chronic oligo/anovulation, and presence of multiple cystic follicles in the ovary. However, the mechanism underlying the abnormal folliculogenesis remains obscure. We have previously demonstrated that CFTR, a cAMP-dependent Cl(-) and HCO3 (-) conducting anion channel, is expressed in the granulosa cells and its expression is downregulated in PCOS rat models and human patients. In this study, we aimed to investigate the possible involvement of downregulation of CFTR in the impaired follicle development in PCOS using two rat PCOS models and primary culture of granulosa cells. Our results indicated that the downregulation of CFTR in the cystic follicles was accompanied by reduced expression of proliferating cell nuclear antigen (PCNA), in rat PCOS models. In addition, knockdown or inhibition of CFTR in granulosa cell culture resulted in reduced cell viability and downregulation of PCNA. We further demonstrated that CFTR regulated both basal and FSH-stimulated granulosa cell proliferation through the HCO3 (-)/sAC/PKA pathway leading to ERK phosphorylation and its downstream target cyclin D2 (Ccnd2) upregulation. Reduced ERK phosphorylation and CCND2 were found in ovaries of rat PCOS model compared with the control. This study suggests that CFTR is required for normal follicle development and that its downregulation in PCOS may inhibit granulosa cell proliferation, resulting in abnormal follicle development in PCOS.
authors: Faculty of MedicineSchool of Biomedical Sciences, Epithelial Cell Biology Research Center, CUHK-SJTU Joint Center for Human Reproduction and Related Diseases, The Chinese University of Hong Kong, Sha Tin, New Territories, Hong Kong.
authors: Hui
authors: H
authors: Chen
authors: Faculty of MedicineSchool of Biomedical Sciences, Epithelial Cell Biology Research Center, CUHK-SJTU Joint Center for Human Reproduction and Related Diseases, The Chinese University of Hong Kong, Sha Tin, New Territories, Hong Kong.
authors: Jing Hui
authors: JH
authors: Guo
authors: Faculty of MedicineSchool of Biomedical Sciences, Epithelial Cell Biology Research Center, CUHK-SJTU Joint Center for Human Reproduction and Related Diseases, The Chinese University of Hong Kong, Sha Tin, New Territories, Hong Kong.
authors: Xiao Hu
authors: XH
authors: Zhang
authors: Faculty of MedicineSchool of Biomedical Sciences, Epithelial Cell Biology Research Center, CUHK-SJTU Joint Center for Human Reproduction and Related Diseases, The Chinese University of Hong Kong, Sha Tin, New Territories, Hong Kong hsiaocchan@cuhk.edu.hk.
authors: Hsiao Chang
authors: HC
authors: Chan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006107:Granulosa Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D006080:Ovarian Follicle / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011085:Polycystic Ovary Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019005:Cystic Fibrosis Transmembrane Conductance Regulator