{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T03:39:58Z","timestamp":1784345998849,"version":"3.55.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2015,5,1]],"date-time":"2015-05-01T00:00:00Z","timestamp":1430438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["rep.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2212 and HCO3\u2212 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\u2212\/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.<\/jats:p>","DOI":"10.1530\/rep-14-0368","type":"journal-article","created":{"date-parts":[[2015,2,2]],"date-time":"2015-02-02T21:37:41Z","timestamp":1422913061000},"page":"393-401","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":23,"title":["Defective CFTR-regulated granulosa cell proliferation in polycystic ovarian syndrome"],"prefix":"10.1093","volume":"149","author":[{"given":"Hui","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Hui","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao Hu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiao Chang","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,5,1]]},"reference":[{"key":"2026010712410761600_bib1","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1111\/j.1651-2227.2003.tb02571.x","article-title":"Pubertal growth and development in cystic fibrosis: a retrospective review","volume":"92","author":"Aswani","year":"2003","journal-title":"Acta Paediatrica"},{"key":"2026010712410761600_bib2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1385\/ENDO:30:1:3","article-title":"Diagnostic criteria for polycystic ovarian syndrome","volume":"30","author":"Broekmans","year":"2006","journal-title":"Endocrine"},{"key":"2026010712410761600_bib3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s00232-001-0117-y","article-title":"Distribution and regulation of ENaC subunit and CFTR mRNA expression in murine female reproductive tract","volume":"185","author":"Chan","year":"2002","journal-title":"Journal of Membrane Biology"},{"key":"2026010712410761600_bib4","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1126\/science.289.5479.625","article-title":"Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor. [see comment]","volume":"289","author":"Chen","year":"2000","journal-title":"Science"},{"key":"2026010712410761600_bib5","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1093\/humupd\/dms027","article-title":"Regulation of male fertility by CFTR and implications in male infertility","volume":"18","author":"Chen","year":"2012","journal-title":"Human Reproduction Update"},{"key":"2026010712410761600_bib6","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1210\/jc.2011-1363","article-title":"Impaired CFTR-dependent amplification of FSH-stimulated estrogen production in cystic fibrosis and PCOS","volume":"97","author":"Chen","year":"2012","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2026010712410761600_bib8","doi-asserted-by":"crossref","first-page":"7167","DOI":"10.1074\/jbc.M203901200","article-title":"Follicle-stimulating hormone activates extracellular signal-regulated kinase but not extracellular signal-regulated kinase kinase through a 100-kDa phosphotyrosine phosphatase","volume":"278","author":"Cottom","year":"2003","journal-title":"Journal of Biological Chemistry"},{"key":"2026010712410761600_bib9","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1210\/jc.2007-1650","article-title":"Granulosa cell survival and proliferation are altered in polycystic ovary syndrome","volume":"93","author":"Das","year":"2008","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2026010712410761600_bib10","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1210\/er.2009-0012","article-title":"The mammalian ovary from genesis to revelation","volume":"30","author":"Edson","year":"2009","journal-title":"Endocrine Reviews"},{"key":"2026010712410761600_bib11","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1095\/biolreprod.112.105106","article-title":"Regulation of cyclin D2 expression and degradation by follicle-stimulating hormone during rat granulosa cell proliferation in vitro","volume":"88","author":"Han","year":"2013","journal-title":"Biology of Reproduction"},{"key":"2026010712410761600_bib12","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1016\/j.cellsig.2006.02.011","article-title":"FSH signaling pathways in immature granulosa cells that regulate target gene expression: branching out from protein kinase A","volume":"18","author":"Hunzicker-Dunn","year":"2006","journal-title":"Cellular Signalling"},{"key":"2026010712410761600_bib13","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1093\/humupd\/dmi001","article-title":"Apoptosis in the ovary: molecular mechanisms","volume":"11","author":"Hussein","year":"2005","journal-title":"Human Reproduction Update"},{"key":"2026010712410761600_bib14","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/S0093-691X(00)00423-4","article-title":"Immunocytochemical study of cell proliferation in the cystic ovarian follicles in cows","volume":"54","author":"Isobe","year":"2000","journal-title":"Theriogenology"},{"key":"2026010712410761600_bib15","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1210\/en.2003-1029","article-title":"Inhibition of extracellular signal-regulated protein kinase-2 phosphorylation by dihydrotestosterone reduces follicle-stimulating hormone-mediated cyclin D2 messenger ribonucleic acid expression in rat granulosa cells","volume":"145","author":"Kayampilly","year":"2004","journal-title":"Endocrinology"},{"key":"2026010712410761600_bib17","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1126\/science.2570460","article-title":"Identification of the cystic fibrosis gene: genetic analysis","volume":"245","author":"Kerem","year":"1989","journal-title":"Science"},{"key":"2026010712410761600_bib18","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/ng0297-201","article-title":"Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility","volume":"15","author":"Kumar","year":"1997","journal-title":"Nature Genetics"},{"key":"2026010712410761600_bib19","doi-asserted-by":"crossref","first-page":"F435","DOI":"10.1152\/ajprenal.00286.2009","article-title":"CFTR mediates apoptotic volume decrease and cell death by controlling glutathione efflux and ROS production in cultured mice proximal tubules","volume":"298","author":"l'Hoste","year":"2010","journal-title":"American Journal of Physiology. Renal Physiology"},{"key":"2026010712410761600_bib20","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1085\/jgp.200409059","article-title":"Discovery of glycine hydrazide pore-occluding CFTR inhibitors: mechanism, structure\u2013activity analysis, and in vivo efficacy","volume":"124","author":"Muanprasat","year":"2004","journal-title":"Journal of General Physiology"},{"key":"2026010712410761600_bib21","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1095\/biolreprod.105.049486","article-title":"Transcriptional regulation of cyclin D2 by the PKA pathway and inducible cAMP early repressor in granulosa cells","volume":"75","author":"Muniz","year":"2006","journal-title":"Biology of Reproduction"},{"key":"2026010712410761600_bib22","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1165\/rcmb.2008-0264OC","article-title":"CFTR regulation of intracellular pH and ceramides is required for lung endothelial cell apoptosis","volume":"41","author":"Noe","year":"2009","journal-title":"American Journal of Respiratory Cell and Molecular Biology"},{"key":"2026010712410761600_bib23","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0140-6736(07)61345-2","article-title":"Polycystic ovary syndrome","volume":"370","author":"Norman","year":"2007","journal-title":"Lancet"},{"key":"2026010712410761600_bib24","doi-asserted-by":"crossref","first-page":"2944","DOI":"10.1093\/humrep\/deq275","article-title":"Understanding follicle growth in vivo","volume":"25","author":"Oktem","year":"2010","journal-title":"Human Reproduction"},{"key":"2026010712410761600_bib25","doi-asserted-by":"crossref","first-page":"9135","DOI":"10.1074\/jbc.M409486200","article-title":"Induction of cyclin D2 in rat granulosa cells requires FSH-dependent relief from FOXO1 repression coupled with positive signals from Smad","volume":"280","author":"Park","year":"2005","journal-title":"Journal of Biological Chemistry"},{"key":"2026010712410761600_bib26","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1126\/science.2475911","article-title":"Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA","volume":"245","author":"Riordan","year":"1989","journal-title":"Science"},{"key":"2026010712410761600_bib27","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1210\/mend.12.7.0138","article-title":"Hormone-induced proliferation and differentiation of granulosa cells: a coordinated balance of the cell cycle regulators cyclin D2 and p27Kip1","volume":"12","author":"Robker","year":"1998","journal-title":"Molecular Endocrinology"},{"key":"2026010712410761600_bib28","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1095\/biolreprod59.3.476","article-title":"Hormonal control of the cell cycle in ovarian cells: proliferation versus differentiation","volume":"59","author":"Robker","year":"1998","journal-title":"Biology of Reproduction"},{"key":"2026010712410761600_bib29","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1126\/science.2772657","article-title":"Identification of the cystic fibrosis gene: chromosome walking and jumping","volume":"245","author":"Rommens","year":"1989","journal-title":"Science"},{"key":"2026010712410761600_bib30","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/1477-7827-7-68","article-title":"An imbalance between apoptosis and proliferation contributes to follicular persistence in polycystic ovaries in rats","volume":"7","author":"Salvetti","year":"2009","journal-title":"Reproductive Biology and Endocrinology"},{"key":"2026010712410761600_bib31","doi-asserted-by":"crossref","first-page":"439","DOI":"10.7863\/jum.1983.2.10.439","article-title":"Cystic ovaries in cystic fibrosis: an ultrasound and autopsy study","volume":"2","author":"Shawker","year":"1983","journal-title":"Journal of Ultrasound in Medicine"},{"key":"2026010712410761600_bib32","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1365-2265.1987.tb00776.x","article-title":"Amenorrhoea in cystic fibrosis","volume":"26","author":"Stead","year":"1987","journal-title":"Clinical Endocrinology"},{"key":"2026010712410761600_bib33","doi-asserted-by":"crossref","first-page":"4418","DOI":"10.1210\/jc.2007-0729","article-title":"Abnormal preantral folliculogenesis in polycystic ovaries is associated with increased granulosa cell division","volume":"92","author":"Stubbs","year":"2007","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2026010712410761600_bib34","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1093\/oxfordjournals.humrep.a019405","article-title":"Immunohistochemical study of steroidogenesis and cell proliferation in polycystic ovarian syndrome","volume":"11","author":"Takayama","year":"1996","journal-title":"Human Reproduction"},{"key":"2026010712410761600_bib35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1385\/ENDO:30:1:1","article-title":"Polycystic ovarian syndrome: insights into the enigma that is PCOS today","volume":"30","author":"Teede","year":"2006","journal-title":"Endocrine"},{"key":"2026010712410761600_bib36","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/ng0293-157","article-title":"CFTR expression is regulated during both the cycle of the seminiferous epithelium and the oestrous cycle of rodents","volume":"3","author":"Trezise","year":"1993","journal-title":"Nature Genetics"},{"key":"2026010712410761600_bib37","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1038\/ncb1047","article-title":"Involvement of CFTR in uterine bicarbonate secretion and the fertilizing capacity of sperm","volume":"5","author":"Wang","year":"2003","journal-title":"Nature Cell Biology"},{"key":"2026010712410761600_bib38","doi-asserted-by":"crossref","first-page":"9816","DOI":"10.1073\/pnas.0609253104","article-title":"Cystic fibrosis transmembrane conductance regulator is vital to sperm fertilizing capacity and male fertility","volume":"104","author":"Xu","year":"2007","journal-title":"PNAS"},{"key":"2026010712410761600_bib39","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1016\/j.fertnstert.2011.02.036","article-title":"Abnormally enhanced cystic fibrosis transmembrane conductance regulator-mediated apoptosis in endometrial cells contributes to impaired embryo implantation in controlled ovarian hyperstimulation","volume":"95","author":"Yang","year":"2011","journal-title":"Fertility and Sterility"}],"container-title":["Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rep.bioscientifica.com\/view\/journals\/rep\/149\/5\/393.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/149\/5\/393\/64132812\/393.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/149\/5\/393\/64132812\/393.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T17:41:32Z","timestamp":1767807692000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/reproduction\/article\/149\/5\/393\/8236054"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,5,1]]},"references-count":37,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,5,1]]}},"URL":"https:\/\/doi.org\/10.1530\/rep-14-0368","relation":{},"ISSN":["1470-1626","1741-7899"],"issn-type":[{"value":"1470-1626","type":"print"},{"value":"1741-7899","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,5,1]]},"published":{"date-parts":[[2015,5,1]]}}}