The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer.
The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer.
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DOI：
10.1016/j.eururo.2015.10.042
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发表时间：
2016-08
期刊：
影响因子：
23.4
通讯作者：
Neal DE
中科院分区：
文献类型：
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作者：
Shaw GL;Whitaker H;Corcoran M;Dunning MJ;Luxton H;Kay J;Massie CE;Miller JL;Lamb AD;Ross-Adams H;Russell R;Nelson AW;Eldridge MD;Lynch AG;Ramos-Montoya A;Mills IG;Taylor AE;Arlt W;Shah N;Warren AY;Neal DE
雄激素受体(AR)是前列腺癌(PCa)的主要生长因子。因此，了解ARs如何调控人类转录组是至关重要的。去势对人前列腺癌的早期影响以前还没有研究过，27名患者在根治性前列腺癌切除术前7天用去势药物进行了医学上的去势。我们使用质谱学、免疫组织化学和基因表达阵列(通过逆转录-聚合酶链式反应验证)来比较切除的肿瘤和匹配的、对照的、未经治疗的前列腺癌组织。所有患者都有血清雄激素水平，其中前列腺摘除时前列腺内雄激素水平降低。我们观察到已知的雄激素调节基因(TMPRSS2、KLK3、CAMKK2、FKBP5)的差异表达。我们发现去势后有749个基因表达下调，908个基因表达上调。AR对α-甲酰辅酶A外消旋酶和其他三个基因(FAM129A、RAB27A和KIAA0101)的表达进行了调节。雌激素受体1(ESR1)在恶性上皮细胞中表达上调，与ESR1调控基因的差异表达有关，与细胞增殖(Ki-67表达)相关。这项首次以人为本的研究确定了去势后前列腺癌(PCa)发生的快速基因表达变化。雄激素受体调控基因的表达水平可以预测治疗结果。雌激素受体1的上调是前列腺癌细胞在去势后存活的一种机制。这项首次以人为本的研究确定了去势后前列腺癌(PCa)发生的快速基因表达变化。ESR1的上调是PCa细胞即使去势也能存活的一种机制。
The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression). This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration. This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Upregulation of ESR1 is a mechanism by which PCa cells may survive despite castration.