Hendriksen Peter J M, Dits Natasja F J, Kokame Koichi, Veldhoven Antoine, van Weerden Wytske M, Bangma Chris H, Trapman Jan, Jenster Guido
Departments of Urology and Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, the Netherlands.
Cancer Res. 2006 May 15;66(10):5012-20. doi: 10.1158/0008-5472.CAN-05-3082.
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 HERPUD1, 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.
本研究聚焦于雄激素受体通路的选择性适应性变化在前列腺癌发生和发展中的潜在作用。我们通过筛选在前列腺癌细胞系和/或异种移植模型中对雄激素有反应的200个基因来定义雄激素受体通路。然后，利用该雄激素受体通路基因特征对前列腺癌异种移植模型和患者来源样本进行分析。与正常前列腺相比，约一半的雄激素受体通路基因在高分化前列腺癌中上调。在高级别癌症中，雄激素受体通路功能不同的部分被特异性下调。出乎意料的是，转移灶中绝大多数雄激素受体通路基因表达下调。对于一些雄激素受体调控基因，已证实雄激素受体通路基因这种逐渐下调的重要性。原发性前列腺肿瘤中HERPUD1、STK39、DHCR24和SOCS2的mRNA表达较低与根治性前列腺切除术后转移发生率较高相关。HERPUD1 mRNA表达几乎能完美预测转移的发生。体外实验表明，应激反应基因HERPUD1的过表达可迅速诱导细胞凋亡。基于不同亚组内基因的功能，我们提出以下模型。增强的雄激素受体活性参与前列腺癌的早期阶段。在高分化前列腺癌中，雄激素受体激活促进生长以及抑制生长和细胞分化的基因，导致生长速率较低。从低级别到高级别前列腺癌以及转移的进展是由雄激素受体靶基因的选择性下调介导的，这些基因抑制增殖、诱导分化或介导凋亡。
