Androgen regulated genes in human prostate xenografts in mice: relation to BPH and prostate cancer.
Androgen regulated genes in human prostate xenografts in mice: relation to BPH and prostate cancer.
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DOI：
10.1371/journal.pone.0008384
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发表时间：
2009-12-21
期刊：
影响因子：
3.7
通讯作者：
Hayward SW
中科院分区：
文献类型：
--
作者：
Love HD;Booton SE;Boone BE;Breyer JP;Koyama T;Revelo MP;Shappell SB;Smith JR;Hayward SW
良性前列腺增生（BPH）和前列腺癌（CaP）与衰老和雄激素的存在有关，这表明雄激素调节基因在这些常见疾病中起主要作用。雄激素对前列腺生长和发育的调节依赖于完整上皮-间质相互作用的存在。此外，前列腺基质与BPH有关。这表明上皮细胞系不足以鉴定可能导致BPH和CaP并可作为潜在临床生物标志物的雄激素调节基因。在这项研究中，我们使用了人类前列腺异种移植模型，以确定在体内由雄激素调控的基因谱，重点是确定候选生物标志物。将来自根治性前列腺切除术的良性移行区（TZ）人前列腺组织移植到完整或去势雄性免疫缺陷小鼠的肾包膜下部位，然后分别去除或添加雄激素。来自这些组织的RNA的微阵列分析用于鉴定以下基因：1）在前列腺中高度表达，2）响应于雄激素具有显著表达变化，以及3）编码细胞外蛋白。选择符合这些标准的总共95个基因，使用定量实时PCR分析和验证患者前列腺组织中的表达。这些基因的表达水平在来自人前列腺组织的合并RNA中测量，所述人前列腺组织具有不同的BPH病理变化严重程度和不同Gleason评分的CaP。一些雄激素调节基因被确定。此外，这些基因的一个子集在来自临床BPH组织的RNA中过表达，并且发现许多基因的水平与疾病状态相关。我们的研究结果表明，使用小鼠异种移植模型来表征完整的人前列腺组织的雄激素调节的表达谱的可行性和一些问题。
Benign prostatic hyperplasia (BPH) and prostate carcinoma (CaP) are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ) human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1) highly expressed in prostate, 2) had significant expression changes in response to androgens, and, 3) encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues.
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