Androgen receptor is causally involved in the homeostasis of the human prostate endothelial cell
Androgen receptor is causally involved in the homeostasis of the human prostate endothelial cell
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DOI：
10.1210/en.2007-1078
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发表时间：
2008-06-01
期刊：
影响因子：
4.8
通讯作者：
Smith, Gary J.
中科院分区：
文献类型：
--
作者：
Godoy, Alejandro;Watts, Anica;Smith, Gary J.
雄激素剥夺导致前列腺血流量减少，导致上皮细胞暂时凋亡。前列腺内皮细胞对雄激素剥夺的急性反应表明它们是雄激素的主要靶点。然而，据报道，大鼠前列腺内皮细胞不表达雄激素受体（AR），雄激素轴在人前列腺内皮细胞（HPEC）稳态中的作用尚不清楚。本研究在良性前列腺和前列腺癌临床标本的体内HPEC中检测到AR的表达，并通过静脉注射腺病毒小鼠乳腺肿瘤病毒驱动荧光素酶表达载体，证实了AR作为转录因子在严重联合免疫缺陷小鼠移植的人良性前列腺组织原发异种移植物HPEC中起作用。在体外原代培养的HPEC中，共表达CD31、CD34、血管性血液病因子、细胞间粘附分子、血管内皮生长因子受体1和血管内皮生长因子受体2，但不表达前列腺特异性抗原，AR的表达和功能保持不变。利用RT-PCR、cDNA测序、免疫细胞化学和Western blot分析验证了良性前列腺手术标本中分离的HPEC原代培养物中AR的表达。Scatchard分析显示，在HPEC原代培养中，R1881有一个单一的配体结合位点，解离常数为0.25 nM，使用腺病毒小鼠乳腺肿瘤病毒驱动的荧光素酶报告基因证实了ar介导的转录活性。在Matrigel中，双氢睾酮以剂量依赖的方式增加了HPEC原代培养物的增殖，而不调节内皮管的形成（BD Biosciences, Bedford， MA）。因此，HPEC表达功能性AR，雄激素在HPEC生物学调控中起直接作用。
Androgen deprivation causes a reduction of blood flow in the prostate gland that precedes temporally apoptosis of the epithelium. The acute response of prostate endothelial cells to androgen deprivation suggested they represent a primary target for androgen. However, rat prostate endothelial cells were reported not to express androgen receptor (AR), and the role of the androgen axis in human prostate endothelial cell (HPEC) homeostasis was poorly characterized. In this study AR expression was detected in HPEC in vivo in clinical specimens of benign prostate and prostate cancer, and AR function as a transcription factor was demonstrated in HPEC in primary xenografts of human benign prostate tissue transplanted into severe combined immunodeficient mice by iv administration of adenoviral mouse mammary tumor virus-driven luciferase expression vector. AR expression and functionality were maintained in vitro in primary cultures of HPEC that coexpressed CD31, CD34, von Willebrand factor,intercellular adhesion molecule, vascular endothelial growth factor receptor 1, and vascular endothelial growth factor receptor 2 but did not express prostate-specific antigen. AR expression in primary cultures of HPEC isolated from surgical specimens of benign prostate was validated using RT-PCR, cDNA sequencing, immunocytochemistry, and Western blot analyses. Scatchard analyses demonstrated a single ligand-binding site for R1881 in primary cultures of HPEC, with dissociation constant of 0.25 nM, and AR-mediated transcriptional activity was demonstrated using adenoviral mouse mammary tumor virus-driven luciferase reporters. Dihydrotestosterone increased proliferation in primary cultures of HPEC in a dose-dependent manner without modulating endothelial tube formation in Matrigel (BD Biosciences, Bedford, MA). Therefore, HPECs express functional AR, and androgen plays a direct role in modulating HPEC biology.