Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland.
Prostate. 2014 Jan;74(1):70-89. doi: 10.1002/pros.22731. Epub 2013 Sep 21.
Gene fusion between TMPRSS2 promoter and the ERG proto-oncogene is a major genomic alteration found in over half of prostate cancers (CaP), which leads to aberrant androgen dependent ERG expression. Despite extensive analysis for the biological functions of ERG in CaP, there is no systematic evaluation of the ERG responsive proteome (ERP). ERP has the potential to define new biomarkers and therapeutic targets for prostate tumors stratified by ERG expression.
Global proteome analysis was performed by using ERG (+) and ERG (-) CaP cells isolated by ERG immunohistochemistry defined laser capture microdissection and by using TMPRSS2-ERG positive VCaP cells treated with ERG and control siRNA.
We identified 1,196 and 2,190 unique proteins stratified by ERG status from prostate tumors and VCaP cells, respectively. Comparative analysis of these two proteomes identified 330 concordantly regulated proteins characterizing enrichment of pathways modulating cytoskeletal and actin reorganization, cell migration, protein biosynthesis, and proteasome and ER-associated protein degradation. ERPs unique for ERG (+) tumors reveal enrichment for cell growth and survival pathways while proteasome and redox function pathways were enriched in ERPs unique for ERG (-) tumors. Meta-analysis of ERPs against CaP gene expression data revealed that Myosin VI and Monoamine oxidase A were positively and negatively correlated to ERG expression, respectively.
This study delineates the global proteome for prostate tumors stratified by ERG expression status. The ERP data confirm the functions of ERG in inhibiting cell differentiation and activating cell growth, and identify potentially novel biomarkers and therapeutic targets.
TMPRSS2 启动子与 ERG 原癌基因之间的基因融合是超过一半前列腺癌（CaP）中发现的主要基因组改变，导致异常的雄激素依赖性 ERG 表达。尽管对 ERG 在 CaP 中的生物学功能进行了广泛分析，但对 ERG 反应性蛋白质组（ERP）没有进行系统评估。ERP 有可能为根据 ERG 表达分层的前列腺肿瘤定义新的生物标志物和治疗靶点。
通过使用 ERG（+）和 ERG（-）CaP 细胞进行全蛋白质组分析，这些细胞是通过 ERG 免疫组织化学定义的激光捕获显微切割分离的，并且使用 TMPRSS2-ERG 阳性 VCaP 细胞用 ERG 和对照 siRNA 处理。
我们分别从前列腺肿瘤和 VCaP 细胞中按 ERG 状态分层鉴定出 1196 种和 2190 种独特蛋白质。对这两种蛋白质组的比较分析确定了 330 个具有共同调节作用的蛋白质，这些蛋白质特征在于调节细胞骨架和肌动蛋白重排、细胞迁移、蛋白质生物合成以及蛋白酶体和内质网相关蛋白降解的途径富集。ERG（+）肿瘤的 ERPs 独特地揭示了细胞生长和存活途径的富集，而 ERG（-）肿瘤的 ERPs 则富集了蛋白酶体和氧化还原功能途径。对 ERPs 进行的 Meta 分析针对 CaP 基因表达数据表明，肌球蛋白 VI 和单胺氧化酶 A 分别与 ERG 表达呈正相关和负相关。
本研究描绘了按 ERG 表达状态分层的前列腺肿瘤的全蛋白质组。ERP 数据证实了 ERG 抑制细胞分化和激活细胞生长的功能，并确定了潜在的新型生物标志物和治疗靶点。
