Gregory C W, Hamil K G, Kim D, Hall S H, Pretlow T G, Mohler J L, French F S
Department of Pediatrics, The University of North Carolina at Chapel Hill, 27599, USA.
Cancer Res. 1998 Dec 15;58(24):5718-24.
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.
人前列腺癌（CaP）异种移植瘤CWR22可模拟人CaP。CWR22在睾酮刺激的裸鼠中生长，去势后消退，在无睾丸雄激素的情况下5 - 6个月后复发。与雄激素剥夺治疗期间复发的人CaP一样，复发的CWR22表达高水平的雄激素受体（AR）。免疫组织化学、蛋白质印迹和Northern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，这两个人CaP中两个特征明确的雄激素调节基因，在CWR22中是雄激素依赖性的。尽管没有睾丸雄激素，但复发的CWR22中前列腺特异性抗原和人激肽释放酶2 mRNA水平高于去势12天的小鼠中消退的CWR22肿瘤中的水平，且与雄激素刺激的CWR22中的水平相似。其他AR调节基因遵循类似的表达模式。差异表达筛选确定了雄激素对α - 烯醇化酶和α - 微管蛋白以及其他未知mRNA的调节作用。胰岛素样生长因子结合蛋白5、同源盒基因Nkx 3.1、AR共激活因子ARA - 70以及细胞周期基因Cdk1和Cdk2在CWR22中受雄激素调节。在复发的CWR22中，尽管没有睾丸雄激素，但所有这些AR依赖性mRNA的稳态水平与雄激素刺激的CWR22中的相似。雄激素剥夺的复发CWR22中AR和AR调节基因的表达水平与雄激素刺激的CWR22相似，这表明AR在复发的CWR22中具有转录活性。这些AR调节基因的诱导可能在相对缺乏雄激素的情况下增强细胞增殖，但通过AR依赖性机制。或者，在雄激素非依赖性肿瘤中，AR调节基因网络的诱导表达可能源于这些基因共有的非AR转录控制机制。
