Functional Analysis of Steroid hormone orphan receptor in hormone refractory prostate cancer

前列腺特异性抗原(PSA)已被广泛认为是最可靠的肿瘤标志物。最近的免疫组织化学研究表明，前列腺癌组织中PSA染色强度与肿瘤分级呈负相关。这一现象的分子机制尚不清楚。我们阐明了核孤儿受体COUP-TFI和TR3受体在前列腺癌组织中的PSA表达中起关键作用。逆转录聚合酶链式反应(RT-PCR)分析表明，尽管有雄激素的刺激，TR3稳定表达的LNCaP前列腺癌细胞仍低表达PSA。COUP-TFI和TR3受体在前列腺癌组织中也有表达，并且随着PSA表达的降低而逐渐减弱。瞬时转染PSA启动子分析表明，COUP-TFI或TR3受体以剂量依赖的方式抑制PSA转录。原位杂交结果显示，TR3mRNA在高级别前列腺癌组织中高表达。提示高级别前列腺癌组织中COUP-TFI或TR3受体的高表达可能是通过抑制PSA转录而降低PSA的表达。

Prostate specific antigen (PSA) has been widely recognized as a most reliable tumor marker. A recent report of immunohistochemistry has demonstrated the inverse correlation between PSA staining intensity and tumor grade in prostate cancer tissues. The molecular mechanism of this phenomenon has been as yet unknown. We elucidated that a nuclear orphan receptor, COUP-TFI and TR3 receptor, had key roles in the PSA expression of prostate cancer tissue. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses revealed that TR3 stable transfectant of LNCaP prostate cancer cells expressed low PSA despite of stimulation of androgen. Also, COUP-TFI and TR3 receptor was expressed in human prostate cancer tissues and tended to diminish coincident with decreased PSA expression. Transient transfection analyses of PSA promoter showed that COUP-TFI or TR3 receptor repressed PSA transcription in a dose-dependent manner. In situ hybridization showed that TR3 mRNA more highly expressed in high-grade prostate cancer tissues. These findings suggest that highly expression of COUP-TFI or TR3 receptor might be attributed to decrease PSA intensity in high-grade prostate cancer tissue through suppressing the PSA transcription.