Androgen receptor-target genes in african american prostate cancer disparities.

IF 2.3 Q3 ONCOLOGY
Prostate Cancer Pub Date : 2013-01-01 Epub Date: 2013-01-10 DOI:10.1155/2013/763569
Bi-Dar Wang, Qi Yang, Kristin Ceniccola, Fernando Bianco, Ramez Andrawis, Thomas Jarrett, Harold Frazier, Steven R Patierno, Norman H Lee
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引用次数: 48

Abstract

The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter analysis revealed that 382 out of 1,188 genes contained cis-acting AR-binding sequences. Chromatin immunoprecipitation confirmed STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A,1 and PIK3CB genes as novel AR targets in PCa disparities. Moreover, functional screens revealed that androgen-stimulated AR binding and upregulation of RHOA, ITGB5, and PIK3CB genes were associated with increased invasive activity of AA PCa cells, as siRNA-mediated knockdown of each gene caused a loss of androgen-stimulated invasion. In summation, our findings demonstrate that transcriptional changes have preferentially occurred in multiple signaling pathways converging ("transcriptional convergence") on AR signaling, thereby contributing to AR-target gene activation and PCa aggressiveness in AAs.

Abstract Image

Abstract Image

Abstract Image

非裔美国人前列腺癌差异中的雄激素受体靶基因。
非裔美国人(AA)的前列腺癌(PCa)发病率和死亡率高于白人美国人(CA)。为了阐明前列腺癌差异的分子机制,我们采用了一种结合基因表达谱、途径和启动子分析的综合方法来研究AA和CA癌症的差异转录组和解除调控的信号通路。AA和CA PCa标本的比较鉴定出1188个差异表达基因。有趣的是,这些转录差异在雄激素受体(AR)的信号通路中被过度代表,这表明AR可能是AA型PCa的统一致癌主题。基因启动子分析显示,1188个基因中有382个含有顺式ar结合序列。染色质免疫沉淀证实STAT1、RHOA、ITGB5、MAPKAPK2、CSNK2A、1和PIK3CB基因是PCa差异中新的AR靶点。此外,功能筛选显示雄激素刺激的AR结合和RHOA、ITGB5和PIK3CB基因的上调与AA PCa细胞的侵袭活性增加有关,因为sirna介导的敲低每个基因导致雄激素刺激的侵袭丧失。总之,我们的研究结果表明,转录变化优先发生在聚合AR信号的多个信号通路中(“转录趋同”),从而促进AR靶基因激活和PCa在aa中的侵袭性。
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来源期刊
Prostate Cancer
Prostate Cancer ONCOLOGY-
CiteScore
2.70
自引率
0.00%
发文量
9
审稿时长
13 weeks
期刊介绍: Prostate Cancer is a peer-reviewed, Open Access journal that provides a multidisciplinary platform for scientists, surgeons, oncologists and clinicians working on prostate cancer. The journal publishes original research articles, review articles, and clinical studies related to the diagnosis, surgery, radiotherapy, drug discovery and medical management of the disease.
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