Department of Urology Erasmus Medical Centre, Rotterdam, The Netherlands.
Int J Cancer. 2013 Jul 15;133(2):335-45. doi: 10.1002/ijc.28025. Epub 2013 Feb 12.
Molecular classification of ERG-rearranged prostate cancer clarifies the role of TMPRSS2-ERG in the development and progression of prostate cancer. The objective of our study was to identify direct ERG target genes in ERG-rearranged prostate cancer. Two independent cohorts of primary prostate cancer (Cohort A, n=48; Cohort B, n=31), a cohort of late-stage prostate cancer (n=51) and expression array data of a cohort of primary prostate tumors from a different institute (n=128) were analyzed for expression of genes that were coexpressed with ERG overexpression. By genome-wide expression analysis and Q-RT-PCR it was shown that the gene Tudor domain containing 1 (TDRD1) was by far the strongest correlated gene with ERG overexpression in both Cohort A and B. Expression array analysis of the patient cohort from a different institute showed a large overlap in genes that were positively correlated with ERG overexpression, including TDRD1. In late-stage prostate cancer, TDRD1 was also coexpressed with ERG overexpression, although a proportion of ERG-negative late-stage samples expressed TDRD1. TDRD1 expression was not associated with ETV1 overexpression. In the prostate cancer cell line VCaP, downregulation of ERG by shRNA lead to a lower expression level of TDRD1 and resulted in a decreased activity of the TDRD1 promoter. By mutation analysis we identified a functional ERG binding site in the TDRD1 promoter. Our findings show TDRD1 as the first identified upregulated direct ERG target gene that is strongly associated with ERG overexpression in primary prostate cancer.
ERG 重排前列腺癌的分子分类阐明了 TMPRSS2-ERG 在前列腺癌发生和发展中的作用。我们的研究目的是确定 ERG 重排前列腺癌中 ERG 的直接靶基因。我们分析了两个独立的原发性前列腺癌队列（队列 A，n=48；队列 B，n=31）、一个晚期前列腺癌队列（n=51）和一个来自不同机构的原发性前列腺肿瘤表达数组数据（n=128），以确定与 ERG 过表达共表达的基因的表达。通过全基因组表达分析和 Q-RT-PCR 表明，Tudor 结构域包含 1 号基因（TDRD1）是队列 A 和 B 中与 ERG 过表达相关性最强的基因。来自不同机构的患者队列的表达数组分析显示，与 ERG 过表达呈正相关的基因有很大的重叠，包括 TDRD1。在晚期前列腺癌中，TDRD1 也与 ERG 过表达共表达，尽管一部分 ERG 阴性的晚期样本表达 TDRD1。TDRD1 的表达与 ETV1 过表达无关。在前列腺癌细胞系 VCaP 中，shRNA 下调 ERG 导致 TDRD1 的表达水平降低，并导致 TDRD1 启动子活性降低。通过突变分析，我们在 TDRD1 启动子中鉴定了一个功能性的 ERG 结合位点。我们的研究结果表明 TDRD1 是第一个被确定的上调的直接 ERG 靶基因，它与原发性前列腺癌中 ERG 的过表达密切相关。
