BPH-1通过分泌PGE2上调前列腺间质细胞ERRα的表达

摘要 雌激素受体相关受体α（estrogen receptor-related receptor α，ERRα）是一类可以直接或间接参与雌激素应答反应的孤儿核受体，它与雌激素受体（estrogen receptor）在结构上有很强的同源性．雌激素效应在良性前列腺增生（benign prostatic hyperplasis，BPH）的发生和发展中起着重要的作用．通常，孤儿核受体的转录活性多受一些非经典激素如维生素A衍生物、前列腺素类、固醇的调控．本文研究前列腺上皮细胞分泌的活性因子对间质细胞ERRα表达调控的分子机制．收集前列腺增生上皮细胞系BPH-1和前列腺癌上皮细胞系DU-145的条件培养液（condition medium，CM）培养的间质细胞，采用实时定量RT-PCR和Western 印迹法检测前列腺间质细胞（prostate stromal cells，PrSCs）中ERRα的表达，筛选CM中影响ERRα表达的活性因子．研究结果显示，BPH-1的CM可以上调ERRα的表达，而DU-145的CM对ERRα的表达没有影响；BPH-1中合成前列腺素E2 (prostaglandin E2, PGE2)的限速酶——环氧合酶2（cyclooxygenase-2, COX-2）的mRNA表达水平和PGE2的分泌水平明显高于DU-145中COX-2表达水平和PGE2分泌水平；用经添加COX-2抑制剂NS-398的培养液处理BPH-1，其CM中PGE2的浓度明显下降，并失去了对ERRα表达的上调作用；添加PGE2可上调间质细胞中ERRα的表达．结果表明，BPH-1通过分泌PGE2促进间质细胞ERRa的表达，提示：在良性前列腺增生的发生和发展中，上皮细胞的旁分泌作用可促进间质细胞由ERRα介导的雌激素效应．

Prostaglandin E2 Mediates Up-regulation of ERRα Expression with BPH-1 Condition Medium in Prostatic Stromal Cells

Abstract Estrogen receptor-related receptor α（ERRα）is an orphan nuclear hormone receptor that shares significant homology with the estrogen receptors（ERs）and directly or indirectly modulate estrogen pathways ，which play important roles in pathogenesis of benign prostatic hyperplasia (BPH). To study the effects of prostate epithelial cell paracrine on the ERRα expression in prostate stromal cells (PrSCs), conditioned medium (CM) of BPH-1 (a benign prostate hyperplasia epithelial cell line) and DU-145 (a prostate cancer cell line) were collected and used to treat prostatic stromal cells. The expression of ERRα was determined by real-time RT-PCR and Western blotting, and the expressions of cyclooxygenase-2 (COX-2, prostaglandin synthase 2) of prostaglandin E2 (PGE2) was also examined by real-time RT-PCR and ELISA with or without the treatment of BPH-1 and DU-145 CMs. The CM of BPH-1 treated with NS-398 (a specific inhibitor of COX-2) was collected to analyze its effects on the ERRα expression. The results demonstrated that the CM from BPH-1, but not from DU-145, stimulated the mRNA expression of ERRα in PrSCs, which could be blocked by pretreat the CM producing cells with NS-398. The level of COX-2 mRNA, was significantly higher in BPH-1 than DU-145 CM treated, which correlated to the PGE2 secretion accordingly. The concentration of PGE2 in BPH-1 CM wit was reduced by NS-398, and PGE2 alone could stimulate ERRα expression in PrSCs. Our data suggested that BPH-1 CM could induce the ERRα expression by increasing the paracrine of PGE2, and promote the estrogen effect mediated by ERRα in PrSCs.