Attar Erkut, Tokunaga Hideki, Imir Gonca, Yilmaz M Bertan, Redwine David, Putman Michael, Gurates Bilgin, Attar Rukset, Yaegashi Nobuo, Hales Dale B, Bulun Serdar E
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, 303 East Superior Street, 4-123, Chicago, Illinois 60611, USA.
J Clin Endocrinol Metab. 2009 Feb;94(2):623-31. doi: 10.1210/jc.2008-1180. Epub 2008 Nov 11.
Products of at least five specific steroidogenic genes, including steroidogenic acute regulatory protein (StAR), which facilitates the entry of cytosolic cholesterol into the mitochondrion, side chain cleavage P450 enzyme, 3beta-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, and aromatase, which catalyzes the final step, are necessary for the conversion of cholesterol to estrogen. Expression and biological activity of StAR and aromatase were previously demonstrated in endometriosis but not in normal endometrium. Prostaglandin E2 (PGE2) induces aromatase expression via the transcriptional factor steroidogenic factor-1 (SF1) in endometriosis, which is opposed by chicken-ovalbumin upstream-transcription factor (COUP-TF) and Wilms' tumor-1 (WT1) in endometrium.
The aim of the study was to demonstrate a complete steroidogenic pathway leading to estrogen biosynthesis in endometriotic cells and the transcriptional mechanisms that regulate basal and PGE2-stimulated estrogen production in endometriotic cells and endometrium.
Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3beta-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues. PGE2 induced the expression of all steroidogenic genes; production of progesterone, estrone, and estradiol; and StAR promoter activity in endometriotic cells. Overexpression of SF1 induced, whereas COUP-TFII or WT1 suppressed, StAR promoter activity. PGE2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells. COUP-TFII or WT1 binding to both promoters was significantly higher in endometrial compared with endometriotic cells.
Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE2 via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.
至少五种特定类固醇生成基因的产物参与胆固醇向雌激素的转化，这些基因包括促进胞质胆固醇进入线粒体的类固醇生成急性调节蛋白（StAR）、侧链裂解P450酶、3β-羟基类固醇脱氢酶-2、17-羟化酶/17,20-裂解酶以及催化最后一步反应的芳香化酶。此前已在子宫内膜异位症中证实了StAR和芳香化酶的表达及生物学活性，但在正常子宫内膜中未得到证实。在子宫内膜异位症中，前列腺素E2（PGE2）通过转录因子类固醇生成因子-1（SF1）诱导芳香化酶表达，而在子宫内膜中，鸡卵清蛋白上游转录因子（COUP-TF）和威尔姆斯瘤-1（WT1）则对此起拮抗作用。
本研究旨在证明子宫内膜异位症细胞中存在一条完整的类固醇生成途径，该途径可导致雌激素生物合成，并阐明调节子宫内膜异位症细胞和子宫内膜中基础及PGE2刺激的雌激素产生的转录机制。
与正常子宫内膜组织相比，子宫内膜异位症组织中StAR、侧链裂解P450、3β-羟基类固醇脱氢酶-2、17-羟化酶/17,20-裂解酶、芳香化酶和SF1的mRNA水平显著更高。PGE2诱导了子宫内膜异位症细胞中所有类固醇生成基因的表达、孕酮、雌酮和雌二醇的产生以及StAR启动子活性。SF1的过表达诱导了StAR启动子活性，而COUP-TFII或WT1则抑制了该活性。PGE2诱导了SF1与StAR和芳香化酶启动子的协同结合，但降低了子宫内膜异位症细胞中COUP-TFII的结合。与子宫内膜异位症细胞相比，COUP-TFII或WT1与两个启动子的结合在子宫内膜中显著更高。
子宫内膜异位症细胞含有从胆固醇从头合成雌二醇所需的完整类固醇生成基因，PGE2通过增强SF1与StAR和芳香化酶基因启动子的同步结合来刺激这一过程。
