Androgen-dependent alternative mRNA isoform expression in prostate cancer cells.
Androgen-dependent alternative mRNA isoform expression in prostate cancer cells.
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DOI：
10.12688/f1000research.15604.1
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Elliott DJ
中科院分区：
文献类型：
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作者：
Munkley J;Maia TM;Ibarluzea N;Livermore KE;Vodak D;Ehrmann I;James K;Rajan P;Barbosa-Morais NL;Elliott DJ
背景：雄激素类固醇激素是前列腺癌的关键驱动因素。以前的工作表明，雄激素可以驱动替代mRNA亚型的表达以及前列腺癌细胞中的转录变化。然而，雄激素在多大程度上控制替代mRNA亚型以及这些亚型在前列腺肿瘤中如何表达和差异调节尚不清楚。 研究方法：在这里，我们使用RNA-Seq数据来全面识别前列腺癌细胞中雄激素控制下的替代mRNA亚型表达，并分析这些mRNA亚型在临床组织中的表达。 结果：我们的数据表明雄激素主要通过选择启动子来转换mRNA亚型。我们检测到73个雄激素调节的选择性转录事件，包括56个雄激素依赖的选择性启动子的利用，13个雄激素调节的选择性剪接事件，以及4个雄激素调节的选择性3′ mRNA末端。这些事件中有64个是本研究的新事件，26个涉及以前未注释的亚型。我们在一个独立的样本集中通过定量PCR验证了17种替代亚型的雄激素依赖性调节。一些鉴定的mRNA同种型存在于已经与前列腺癌有关的基因中（包括LIG 4、FDFT 1和RELAXIN），或存在于其他癌症中重要的基因中（例如NUP 93和MAT 2A）。重要的是，对TGCA前列腺癌（PRAD）队列中497个肿瘤样本的转录组数据进行分析，确定了13种mRNA亚型（包括TPD 52，TACC 2和NDUFV 3），这些亚型在局部前列腺癌中相对于正常组织受到差异调节，以及3种（OSBPL 1A，CLK 3和TSC 22 D3），这些亚型随Gleason分级和肿瘤分期而显著变化。 结论：我们的研究结果显着增加了前列腺癌中已知雄激素调节亚型的数量，并表明前列腺癌细胞对雄激素的高度复杂反应可能具有临床意义。
Background: Androgen steroid hormones are key drivers of prostate cancer. Previous work has shown that androgens can drive the expression of alternative mRNA isoforms as well as transcriptional changes in prostate cancer cells. Yet to what extent androgens control alternative mRNA isoforms and how these are expressed and differentially regulated in prostate tumours is unknown. Methods: Here we have used RNA-Seq data to globally identify alternative mRNA isoform expression under androgen control in prostate cancer cells, and profiled the expression of these mRNA isoforms in clinical tissue. Results: Our data indicate androgens primarily switch mRNA isoforms through alternative promoter selection. We detected 73 androgen regulated alternative transcription events, including utilisation of 56 androgen-dependent alternative promoters, 13 androgen-regulated alternative splicing events, and selection of 4 androgen-regulated alternative 3′ mRNA ends. 64 of these events are novel to this study, and 26 involve previously unannotated isoforms. We validated androgen dependent regulation of 17 alternative isoforms by quantitative PCR in an independent sample set. Some of the identified mRNA isoforms are in genes already implicated in prostate cancer (including LIG4, FDFT1 and RELAXIN), or in genes important in other cancers (e.g. NUP93 and MAT2A). Importantly, analysis of transcriptome data from 497 tumour samples in the TGCA prostate adenocarcinoma (PRAD) cohort identified 13 mRNA isoforms (including TPD52, TACC2 and NDUFV3) that are differentially regulated in localised prostate cancer relative to normal tissue, and 3 ( OSBPL1A, CLK3 and TSC22D3) which change significantly with Gleason grade and tumour stage. Conclusions: Our findings dramatically increase the number of known androgen regulated isoforms in prostate cancer, and indicate a highly complex response to androgens in prostate cancer cells that could be clinically important.