Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes.
Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes.
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发表时间：
1998-12
期刊：
影响因子：
11.2
通讯作者：
C. Gregory;K. G. Hamil;Desok Kim;S. H. Hall;T. Pretlow;J. Mohler;F. S. French
中科院分区：
文献类型：
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作者：
C. Gregory;K. G. Hamil;Desok Kim;S. H. Hall;T. Pretlow;J. Mohler;F. S. French
人前列腺癌（CaP）异种移植物CWR22模拟人CaP。CWR22在睾丸激素刺激的裸鼠中生长，去势后退化，在睾丸雄激素缺乏的情况下5 - 6个月后复发。与雄激素剥夺治疗期间复发的人CaP一样，复发性CWR22表达高水平的雄激素受体（AR）。免疫组织化学、Western和北方印迹分析表明，雄激素非依赖性CWR22中的AR表达与去势前雄激素依赖性CWR22中的AR表达相似。前列腺特异性抗原和人激肽释放酶-2 mRNA的表达，两个良好的特征性雄激素调节基因在人CaP，CWR22雄激素依赖。尽管没有睾丸雄激素，前列腺特异性抗原和人激肽释放酶-2 mRNA水平复发CWR22高于12天去势小鼠的消退CWR22肿瘤的水平，并与雄激素刺激的CWR22相似。其他AR调节基因遵循类似的表达模式。差异表达筛选鉴定了α-烯醇化酶和α-微管蛋白以及其他未知mRNA的雄激素调节。胰岛素样生长因子结合蛋白-5，同源异型盒基因Nkx 3.1，AR共激活因子ARA-70，细胞周期基因Cdk1和Cdk2在CWR22中受雄激素调节。在复发性CWR22中，所有这些AR依赖性mRNA的稳态水平与雄激素刺激的CWR22中的水平相似，尽管没有睾丸雄激素。AR和AR调节基因在雄激素剥夺的复发性CWR22中的表达水平与雄激素刺激的CWR22相似，表明AR在复发性CWR22中具有转录活性。这些AR调节基因的诱导可能会增强细胞增殖在相对雄激素缺乏，但通过AR依赖性机制。或者，在雄激素非依赖性肿瘤中，AR调节的基因网络的诱导表达可能是由这些基因共同的非AR转录控制机制引起的。
The human prostate cancer (CaP) xenograft, CWR22, mimics human CaP. CWR22 grows in testosterone-stimulated nude mice, regresses after castration, and recurs after 5-6 months in the absence of testicular androgen. Like human CaP that recurs during androgen deprivation therapy, the recurrent CWR22 expresses high levels of androgen receptor (AR). Immunohistochemical, Western, and Northern blot analyses demonstrated that AR expression in the androgen-independent CWR22 is similar to AR expression in the androgen-dependent CWR22 prior to castration. Expression of prostate-specific antigen and human kallikrein-2 mRNAs, two well-characterized androgen-regulated genes in human CaP, was androgen dependent in CWR22. Despite the absence of testicular androgen, prostate-specific antigen and human kallikrein-2 mRNA levels in recurrent CWR22 were higher than the levels in regressing CWR22 tumors from 12-day castrate mice and similar to those in the androgen-stimulated CWR22. Other AR-regulated genes followed a similar pattern of expression. Differential expression screening identified androgen regulation of alpha-enolase and alpha-tubulin as well as other unknown mRNAs. Insulin-like growth factor binding protein-5, the homeobox gene Nkx 3.1, the AR coactivator ARA-70, and cell cycle genes Cdk1 and Cdk2 were androgen regulated in CWR22. In recurrent CWR22, the steady-state levels of all these AR-dependent mRNAs were similar to those in the androgen-stimulated CWR22, despite the absence of testicular androgen. Expression of AR and AR-regulated genes in the androgen-deprived recurrent CWR22 at levels similar to the androgen-stimulated CWR22 suggests that AR is transcriptionally active in recurrent CWR22. Induction of these AR-regulated genes may enhance cellular proliferation in relative androgen absence but through an AR-dependent mechanism. Alternatively, in androgen-independent tumors, induced expression of the AR-regulated gene network might result from a non-AR transcription control mechanism common to these genes.