Qiao Gu-Yuan, Dong Bing-Wei, Zhu Chao-Juan, Yan Chang-You, Chen Bi-Liang
Department of Gynaecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Department of Pathology, Xian Yang Central Hospital, Xian Yang 712000, China.
Biochem Biophys Res Commun. 2017 Nov 4;493(1):847-854. doi: 10.1016/j.bbrc.2017.07.057. Epub 2017 Jul 11.
Mechanistic insight into estrogen deficiency by polycystic ovary syndrome (PCOS) remains a longstanding challenge in reproductive medicine. Recent advance suggest that Wingless-type MMTV integration site family members (WNTs), in concert with its Frizzled (FZD) receptors, regulate normal folliculogenesis, luteogenesis and ovarian steroidogenesis. However, no studies have so far investigated any causality between WNT-FZDs interactions and disrupted estrogen synthesis under certain pathological conditions. Here, we show that (i) FZD3 expression was significantly up-regulated in the cumulus cells (CCs) from PCOS patients. This up-regulation, along with the activation of WNT2/β-Catenin pathway, was tightly associated with insulin resistance and estrogen deficiency, two hallmarks of PCOS. (ii) Overexpression of exogenous FZD3 in human granulosa cell COV434 impaired long-term FSH incubation-induced CYP19A1 transactivation and the recruitment of β-Catenin onto CYP19A1 promoter, and subsequently compromised FSH-stimulated estrogen production. (iii) Conversely, inhibition of FZD3 expression exhibited a therapeutic effect on estrogen synthesis in PCOS CCs. Thus, excessive FZD3 expression in CCs may act as a brake on steroidogenic activation that is normally overcome by FSH stimulation. Future endeavor in this field should help to elucidate the complicated crosstalk between energy metabolism and endocrine cells through WNT/FZD signaling molecules.
多囊卵巢综合征（PCOS）导致雌激素缺乏的机制，仍然是生殖医学领域长期面临的挑战。最近的研究进展表明，无翅型MMTV整合位点家族成员（WNTs）与其卷曲蛋白（FZD）受体协同作用，调节正常的卵泡发生、黄体生成和卵巢类固醇生成。然而，迄今为止，尚无研究探讨在某些病理条件下WNT-FZD相互作用与雌激素合成紊乱之间的因果关系。在此，我们发现：（i）PCOS患者卵丘细胞（CCs）中FZD3表达显著上调。这种上调，连同WNT2/β-连环蛋白通路的激活，与胰岛素抵抗和雌激素缺乏密切相关，这是PCOS的两个特征。（ii）在人颗粒细胞COV434中外源FZD3的过表达损害了长期FSH孵育诱导的CYP19A1反式激活以及β-连环蛋白在CYP19A1启动子上的募集，随后损害了FSH刺激的雌激素产生。（iii）相反，抑制FZD3表达对PCOS CCs中的雌激素合成具有治疗作用。因此，CCs中FZD3的过度表达可能会抑制类固醇生成激活，而这种激活通常会被FSH刺激所克服。该领域未来研究应有助于阐明通过WNT/FZD信号分子，能量代谢与内分泌细胞之间复杂的相互作用。
