Chen Hui, Guo Jing Hui, Zhang Xiao Hu, Chan Hsiao Chang
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.
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
Reproduction. 2015 May;149(5):393-401. doi: 10.1530/REP-14-0368. Epub 2015 Feb 2.
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.
多囊卵巢综合征（PCOS）是女性不孕最常见的原因之一，其特征为激素水平异常、慢性少排卵/无排卵以及卵巢中存在多个囊性卵泡。然而，卵泡发育异常的潜在机制仍不清楚。我们之前已经证明，囊性纤维化跨膜传导调节因子（CFTR），一种依赖环磷酸腺苷（cAMP）的氯离子（Cl⁻）和碳酸氢根离子（HCO₃⁻）传导阴离子通道，在颗粒细胞中表达，并且在PCOS大鼠模型和人类患者中其表达下调。在本研究中，我们旨在使用两种大鼠PCOS模型和颗粒细胞原代培养来研究CFTR下调在PCOS卵泡发育受损中的可能作用。我们的结果表明，在大鼠PCOS模型中，囊性卵泡中CFTR的下调伴随着增殖细胞核抗原（PCNA）表达的降低。此外，在颗粒细胞培养中敲低或抑制CFTR导致细胞活力降低和PCNA下调。我们进一步证明，CFTR通过HCO₃⁻/可溶性腺苷酸环化酶（sAC）/蛋白激酶A（PKA）途径调节基础和促卵泡激素（FSH）刺激的颗粒细胞增殖，导致细胞外信号调节激酶（ERK）磷酸化及其下游靶点细胞周期蛋白D2（Ccnd2）上调。与对照组相比，在大鼠PCOS模型的卵巢中发现ERK磷酸化和CCND2降低。本研究表明，正常卵泡发育需要CFTR，其在PCOS中的下调可能抑制颗粒细胞增殖，导致PCOS卵泡发育异常。
