Evolution of the androgen receptor pathway during progression of prostate cancer
Evolution of the androgen receptor pathway during progression of prostate cancer
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DOI：
10.1158/0008-5472.can-05-3082
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发表时间：
2006-05-15
期刊：
影响因子：
11.2
通讯作者：
Jenster, Guido
中科院分区：
文献类型：
--
作者：
Hendriksen, Peter J. M.;Dits, Natasja F. J.;Jenster, Guido
目前的工作集中在潜在的参与雄激素受体途径的选择性适应在前列腺癌的发生和发展。我们通过选择200个在前列腺癌细胞系和/或异种移植物中对雄激素有反应的基因来定义雄激素受体途径。然后将该雄激素受体途径基因签名用于分析前列腺癌异种移植物和患者来源的样品。与正常前列腺相比，大约一半的雄激素受体途径基因在高分化前列腺癌中上调。雄激素受体途径的功能不同部分在高级别癌症中特异性下调。出乎意料的是，转移已经下调了绝大多数雄激素受体途径基因。雄激素受体途径基因的这种进行性下调的意义在一些雄激素受体调节基因中得到了证实。原发性前列腺肿瘤中HER-PUD 1、STK 39、DHCR 24和SOCS 2的较低mRNA表达与根治性前列腺切除术后较高的转移发生率相关。HERPUD 1 mRNA表达几乎完全预测转移的发生。体外实验表明，过度表达应激反应基因HERPUD 1可迅速诱导细胞凋亡。基于不同子集内基因的功能，我们提出以下模型。前列腺癌的早期阶段与雄激素受体活性增强有关。在分化良好的前列腺癌中，雄激素受体激活生长促进基因以及生长抑制基因和细胞分化基因，导致低生长速率。从低级别到高级别的前列腺癌和转移的进展是由抑制增殖、诱导分化或介导凋亡的雄激素受体靶基因的选择性下调介导的。
The present work focused on the potential involvement of selective adaptations of the androgen receptor pathway in the initiation and progression of prostate cancer. We defined the androgen receptor pathway by selecting 200 genes that were androgen responsive in prostate cancer cell lines and/or xenografts. This androgen receptor pathway gene signature was then used for profiling prostate cancer xenografts and patient-derived samples. Approximately half of the androgen receptor pathway genes were up-regulated in well-differentiated prostate cancer compared with normal prostate. Functionally distinct parts of the androgen receptor pathway were specifically down-regulated in high-grade cancers. Unexpectedly, metastases have down-regulated the vast majority of androgen receptor pathway genes. The significance of this progressive down-regulation of androgen receptor pathway genes was shown for a few androgen receptor-regulated genes. Lower mRNA expression of HER-PUD1, STK39, DHCR24, and SOCS2 in primary prostate tumors was correlated with a higher incidence of metastases after radical prostatectomy. HERPUD1 mRNA expression predicted the occurrence of metastases almost perfectly. In vitro experiments showed that overexpression of the stress response gene HERPUD1 rapidly induces apoptosis. Based on the functions of the genes within the distinct subsets, we propose the following model. Enhanced androgen receptor activity is involved in the early stages of prostate cancer. In well-differentiated prostate cancer, the androgen receptor activates growth-promoting as well as growth-inhibiting and cell differentiation genes resulting in a low growth rate. The progression from low-grade to high-grade prostate carcinoma and metastases is mediated by a selective down-regulation of the androgen receptor target genes that inhibit proliferation, induce differentiation, or mediate apoptosis.