FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development
FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development
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DOI：
10.1210/me.2015-1103
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发表时间：
2015-07-01
影响因子：
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通讯作者：
Richards, JoAnne S.
中科院分区：
文献类型：
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作者：
Liu, Zhilin;Ren, Yi A.;Richards, JoAnne S.
叉头盒（FOX），FOXO 1和FOXO 3，转录因子调节哺乳动物细胞中的多种功能。选择性灭活小鼠卵巢颗粒细胞中的Foxo 1和Foxo 3基因严重损害卵泡发育和凋亡，导致不孕，如图所示，颗粒细胞瘤（GCT）形成。在Foxo 1/3菌株中协同缺失抑癌基因Pten增强了GCT形成的发生率和发病率。免疫染色和蛋白质印迹分析证实了FOXO 1和磷酸酶和张力蛋白同源物（PTEN）的耗尽，珠蛋白转录因子（加塔）4的维持和FOXL 2的核定位以及肿瘤细胞中磷酸化的小母细胞对十肢麻痹（SMAD）2/3的作用，重现了我们在成人GCT中观察到的结果。小鼠GCT的微阵列和定量PCR分析进一步证实了控制颗粒细胞命运特化和增殖的特定基因（Foxl 2，Gata 4和Wnt 4）的表达，而其他基因（Emx 2，Nr 0 b 1，Rsp 1和Wt 1）则受到抑制。控制卵泡生长、凋亡和分化的关键基因（Amh、Bmp 2和Fshr）也受到抑制。Inhbb和Grem 1选择性升高，而Inha的减少提供了额外的证据，即激活素信号传导和小母细胞对十肢麻痹（SMAD）2/3磷酸化影响GCT形成。出乎意料的是，支持细胞/上皮细胞（SRY [性别决定区Y]-框9/角蛋白8）和替代活化的巨噬细胞（几丁质酶3样3）的标记物在小鼠GCT内的离散亚群中升高，表明Foxo 1/3/Pten缺失不仅导致GCT，而且改变了颗粒细胞的命运决定和免疫反应。因此，对Foxo 1/3/Pten小鼠GCT和人类成人GCT的分析提供了强有力的证据，即FOXO 1/3/PTEN途径的功能受损导致颗粒细胞内分子程序的显著变化，在FOXL 2和GATA 4存在下的慢性激活素信号传导，以及肿瘤形成。
The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of FOXL2 and GATA4, and tumor formation.