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

激素难治性前列腺癌中类固醇激素孤儿受体的功能分析

• 批准号: 11671568
• 负责人: UEMURA Hiroji
• 金额: $ 2.37万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671568/
• 关键词: Steroid hormone orphan receptor; prostate cancer; transcription factor; ルシフェラーゼ; スチロイドホルモン・オーファンレセプター; ステロイドホルモン・オーファンレセプター

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.

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。最近的一份免疫组织化学报告证明了前列腺癌组织中 PSA 染色强度与肿瘤分级之间呈负相关。这种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的 PSA 表达中起关键作用。逆转录聚合酶链反应（RT-PCR）分析显示，尽管雄激素刺激，LNCaP前列腺癌细胞的TR3稳定转染子仍表达低PSA。此外，COUP-TFI 和 TR3 受体在人前列腺癌组织中表达，并且随着 PSA 表达的减少而趋于减少。 PSA启动子的瞬时转染分析表明COUP-TFI或TR3受体以剂量依赖性方式抑制PSA转录。原位杂交显示TR3 mRNA在高级别前列腺癌组织中表达更高。这些发现表明，COUP-TFI 或 TR3 受体的高表达可能是通过抑制 PSA 转录来降低高级别前列腺癌组织中 PSA 强度的。

项目成果

Mikata K, Uemura H et al.: "Inhibition of Growth Prostate Cancer Xenograft by Transfection of p53 Gene : Gene Transfer by Electroporation"Molecular Cancer Therapeutics. 1・4. 247-252 (2002)

Mikata K、Uemura H等：“通过p53基因转染抑制前列腺癌异种移植物：通过电穿孔进行基因转移”《分子癌症治疗》1·4(2002)。

Y.Miyoshi, H.Uemura et al.: "Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification"Prostate. 4. 225-232 (2001)

Y.Miyoshi、H.Uemura 等：“c-myc 和雄激素受体基因扩增的荧光原位杂交评估”前列腺。

Y.Miyoshi, H.Uemura, K.Fujinami, K.Mikata, M.Harada, H.Kitamura, Y.Koizumi, Y.Kubota.: "Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients"Prost

Y.Miyoshi、H.Uemura、K.Fujinami、K.Mikata、M.Harada、H.Kitamura、Y.Koizumi、Y.Kubota.：“c-myc 和雄激素受体基因扩增和染色体的荧光原位杂交评估

J.Ohta, Y.Miyoshi, H.Uemura, K.Fujinami, K.Mikata, M.Hosaka, Y.Tokita, Y.Kubota.: "Fluorescence in situ hybridization evaluation of c-erbB-2 gene amplification and chromosomal anomalies in bladder cancer"Clin Cancer Res. 7:8. 2463-2467 (2001)

J.Ohta、Y.Miyoshi、H.Uemura、K.Fujinami、K.Mikata、M.Hosaka、Y.Tokita、Y.Kubota.：“c-erbB-2 基因扩增和染色体异常的荧光原位杂交评估

K.Fukutome, M.Watanabe, T.Shiraishi, M.Murata, H.Uemura, Y.Kubota, J.Kawamura, H.Ito, R.Yatani.: "N-acetyltransferase 1 genetic polymorphism influences the risk of prostate cancer treatment"Cancer Letter. 136:1. 83-87 (1999)

K.Fukutome、M.Watanabe、T.Shiraishi、M.Murata、H.Uemura、Y.Kubota、J.Kawamura、H.Ito、R.Yatani.：“N-乙酰转移酶 1 基因多态性影响前列腺癌的风险