核受体超家族的泛癌分析。

Nuclear Receptor Research Pub Date : 2015-12-01 Epub Date: 2015-12-15 DOI:10.11131/2015/101182
Mark D Long, Moray J Campbell
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引用次数: 42

摘要

核受体(NR)作为环境和激素信号的综合通道,控制与细胞命运决定有关的基因组反应。我们回顾了它们之间的综合作用,共享的辅助因子和其他转录因子在癌症中是如何被破坏的。类固醇激素核受体是乳腺癌和前列腺癌的致癌驱动因素,阻断信号传导是主要的治疗目标。与阻断受体相比,在其他癌症中增强受体功能是有吸引力的,正如最初在白血病中靶向维甲酸受体所说明的那样。在后基因组时代,像癌症基因组图谱这样的大型联盟已经开发了大量的基因组数据,用于在泛癌症方式下检查核受体状态的多个方面。因此,为了扩展NR功能的综述,我们还对分布在6种不同肿瘤类型(膀胱、乳腺、结肠、头颈部、肝脏和前列腺)的3000多种肿瘤中的NR表达进行了生物信息学分析。具体来说,为了了解NR表达是如何扭曲的(表达改变、突变和CNV),我们应用了bootstrapping方法来模拟数据进行比较,并将这些NR发现与其他12个转录因子家族进行了比较。核受体在所有六种肿瘤类型中都是独特而一致的下调,比预测的要多。这些方法还揭示了每种肿瘤类型都有特定的NR表达谱,但这些表达谱在乳腺癌和前列腺癌之间最为相似。一些nrrs在至少五种肿瘤类型中下调(例如NR3C2/MR和NR5A2/LRH-1),而其他nrrs在一种肿瘤中唯一下调(例如NR1B3/RARG)。这种下调不是由拷贝数变异或突变驱动的,可能是表观遗传机制导致的核受体表达改变。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Pan-cancer analyses of the nuclear receptor superfamily.

Pan-cancer analyses of the nuclear receptor superfamily.

Pan-cancer analyses of the nuclear receptor superfamily.

Nuclear receptors (NR) act as an integrated conduit for environmental and hormonal signals to govern genomic responses, which relate to cell fate decisions. We review how their integrated actions with each other, shared co-factors and other transcription factors are disrupted in cancer. Steroid hormone nuclear receptors are oncogenic drivers in breast and prostate cancer and blockade of signaling is a major therapeutic goal. By contrast to blockade of receptors, in other cancers enhanced receptor function is attractive, as illustrated initially with targeting of retinoic acid receptors in leukemia. In the post-genomic era large consortia, such as The Cancer Genome Atlas, have developed a remarkable volume of genomic data with which to examine multiple aspects of nuclear receptor status in a pan-cancer manner. Therefore to extend the review of NR function we have also undertaken bioinformatics analyses of NR expression in over 3000 tumors, spread across six different tumor types (bladder, breast, colon, head and neck, liver and prostate). Specifically, to ask how the NR expression was distorted (altered expression, mutation and CNV) we have applied bootstrapping approaches to simulate data for comparison, and also compared these NR findings to 12 other transcription factor families. Nuclear receptors were uniquely and uniformly downregulated across all six tumor types, more than predicted by chance. These approaches also revealed that each tumor type had a specific NR expression profile but these were most similar between breast and prostate cancer. Some NRs were down-regulated in at least five tumor types (e.g. NR3C2/MR and NR5A2/LRH-1)) whereas others were uniquely down-regulated in one tumor (e.g. NR1B3/RARG). The downregulation was not driven by copy number variation or mutation and epigenetic mechanisms maybe responsible for the altered nuclear receptor expression.

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