Division of Oncology, Department of Histology and Pathology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Prostate. 2010 May 1;70(6):630-45. doi: 10.1002/pros.21097.
Prostate cancer (PrCa) has a high incidence in Western countries and at present, there is no cure for hormone refractory prostate cancer. Transgenic mouse models have proven useful for understanding mechanisms of prostate carcinogenesis. The characterization of genetically modified mouse PrCa models using high-throughput genomic analyses provides important information to guide appropriate experiment applications for such model.
We have analyzed the transcriptome of the hormone refractory and highly metastatic Fetal Globin-SV40/T-antigen (Ggamma-globin-Tag) transgenic mouse model for PrCa compared to normal mouse prostate tissue. Gene expression patterns found in Ggamma-globin-Tag mouse prostate tumors were compared with publicly available human localized and metastatic prostate tumors (GEO accession # GSE3325) through hierarchical cluster analysis, Pearson's rank correlation coefficient, and Self Organizing Feature Maps (SOM) analyses.
Ggamma-globin-Tag tumors clustered closely with human metastatic tumors and gene expression patterns had a significant correlation (P < 0.01), unlike human localized primary tumors (P > 0.6). Bioinformatic analyses identified deregulated genetic pathways and networks in Ggamma-globin-Tag tumors, which displayed similarities to alterations in human PrCa. Changes in the expression of genes involved in DNA replication and repair (Rb1, p53, Myc, PCNA, DNMT3A) and growth factor signaling pathways (TGFbeta2, ERK1/2, NRas, and Notch1) are deregulated in the Ggamma-globin-Tag tumors, suggesting their key role in the oncogenic process. Identification of an enrichment of putative binding sites for transcription factors revealed eight transcription factors that may be important in Ggamma-globin-Tag carcinogenesis, including SP1, NF-Y, CREB, Elk1, and E2F. Novel genes related to microtubule regulation were also identified in Ggamma-globin-Tag tumors as potentially important candidate targets for PrCa. Overexpression of stathmin-1, whose expression was increased in human metastatic prostate tumors, was validated in Ggamma-globin-Tag tumors by immunohistochemistry. This protein belongs to the SV40/T-antigen cancer signature identified in previous studies in prostate, breast, and lung cancer mouse models.
Our results show that the Ggamma-globin-Tag model for hormone refractory PrCa shares important features with aggressive, metastatic human PrCa. Given the role of stathmin-1 in the destabilization of microtubles and taxane resistance, the Ggamma-globin-Tag model and other SV40/T-antigen driven transgenic models may be useful for testing potential therapies directed at stathmin-1 in human prostate tumors.
前列腺癌（PrCa）在西方国家发病率很高，目前对于激素难治性前列腺癌尚无治愈方法。转基因小鼠模型已被证明有助于理解前列腺癌发生的机制。使用高通量基因组分析对遗传修饰的小鼠 PrCa 模型进行特征描述，为此类模型的适当实验应用提供了重要信息。
我们分析了激素难治性和高转移性胎球蛋白-SV40/T 抗原（Gγ-球蛋白-Tag）转基因小鼠模型的转录组，与正常小鼠前列腺组织进行比较。通过层次聚类分析、Pearson 秩相关系数和自组织特征映射（SOM）分析，比较 Gγ-球蛋白-Tag 小鼠前列腺肿瘤中的基因表达模式与公开的人类局限性和转移性前列腺肿瘤（GEO 注册号 GSE3325）。
Gγ-球蛋白-Tag 肿瘤与人类转移性肿瘤聚类密切，基因表达模式具有显著相关性（P < 0.01），而与人类局限性原发性肿瘤（P > 0.6）不同。生物信息学分析鉴定了 Gγ-球蛋白-Tag 肿瘤中失调的遗传途径和网络，这些途径和网络与人类 PrCa 的改变相似。参与 DNA 复制和修复的基因（Rb1、p53、Myc、PCNA、DNMT3A）和生长因子信号通路（TGFβ2、ERK1/2、NRAS 和 Notch1）表达的变化在 Gγ-球蛋白-Tag 肿瘤中失调，表明它们在致癌过程中的关键作用。鉴定转录因子的潜在结合位点的富集揭示了 8 个可能在 Gγ-球蛋白-Tag 癌发生中起重要作用的转录因子，包括 SP1、NF-Y、CREB、Elk1 和 E2F。还在 Gγ-球蛋白-Tag 肿瘤中鉴定了与微管调节相关的新基因，它们可能是 PrCa 的潜在重要候选靶标。Stathmin-1 的过表达在人类转移性前列腺肿瘤中增加，通过免疫组织化学在 Gγ-球蛋白-Tag 肿瘤中得到验证。该蛋白属于以前在前列腺、乳腺和肺癌小鼠模型中研究确定的 SV40/T 抗原癌症特征。
我们的结果表明，激素难治性 PrCa 的 Gγ-球蛋白-Tag 模型与侵袭性、转移性人类 PrCa 具有重要特征。鉴于 stathmin-1 在微管不稳定和紫杉烷耐药中的作用，Gγ-球蛋白-Tag 模型和其他 SV40/T 抗原驱动的转基因模型可能有助于测试针对人类前列腺肿瘤中 stathmin-1 的潜在治疗方法。
