Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis
Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis
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DOI：
10.1210/jc.2008-1180
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发表时间：
2009-02-01
影响因子：
5.8
通讯作者：
Bulun, Serdar E.
中科院分区：
文献类型：
--
作者：
Attar, Erkut;Tokunaga, Hideki;Bulun, Serdar E.
内容：至少五种特定类固醇生成基因的产物，包括促进胞质胆固醇进入雌激素受体的类固醇生成急性调节蛋白（星星）、侧链裂解P450酶、3 β-羟基类固醇脱氢酶-2，17-羟化酶/17-20-裂解酶和催化最后一步的芳香酶，是胆固醇转化为雌激素所必需的。星星和芳香化酶的表达和生物活性在子宫内膜异位症中被证实，但在正常子宫内膜中没有。子宫内膜异位症中前列腺素E-2（PGE（2））通过转录因子类固醇生成因子-1（SF 1）诱导芳香化酶表达，而子宫内膜中鸡卵清蛋白上游转录因子（COUP-TF）和Wilms' tumor-1（WT 1）则与之相反。该研究的目的是证明一个完整的类固醇合成途径，导致雌激素生物合成的细胞和转录机制，调节子宫内膜异位细胞和子宫内膜中基础雌激素和PGE（2）刺激的雌激素产生。结果：与正常子宫内膜组织相比，子宫内膜异位组织中星星、侧链切割P450、3 β-羟类固醇脱氢酶-2，17-羟化酶/17-20-裂合酶、芳香酶和SF 1的mRNA水平明显升高。PGE（2）诱导所有类固醇基因的表达;孕酮、雌酮和雌二醇的产生;以及星星启动子在卵巢癌细胞中的活性。SF 1的过表达诱导，而COUP-TFII或WT 1抑制，星星启动子活性。PGE（2）诱导SF 1与星星和芳香化酶启动子的配位结合，但降低COUP-TFII在细胞中的结合。结论：子宫内膜异位症细胞中含有完整的甾体激素合成基因，PGE（2）通过增强SF 1与星星和芳香化酶基因启动子的同步结合，促进了雌激素合成。（临床内分泌代谢杂志94：623-631，2009）
Context: 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, 3 beta-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 E-2 (PGE(2)) 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.Objective: 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 PGE(2)-stimulated estrogen production in endometriotic cells and endometrium.Results: Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3 beta-hydroxysteroid- dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues. PGE(2) 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. PGE(2) 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.Conclusion: Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE(2) via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion. (J Clin Endocrinol Metab 94: 623-631, 2009)