Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer.
Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer.
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DOI：
10.1158/0008-5472.can-08-2764
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发表时间：
2009-01-01
期刊：
影响因子：
11.2
通讯作者：
Luo J
中科院分区：
文献类型：
--
作者：
Hu R;Dunn TA;Wei S;Isharwal S;Veltri RW;Humphreys E;Han M;Partin AW;Vessella RL;Isaacs WB;Bova GS;Luo J
雄激素产生和功能的抑制可缓解但不能治愈前列腺癌（PCa）患者。治疗失败和进展为激素难治性前列腺癌（HRPC）通常伴随着涉及雄激素受体（AR）的分子改变。在这项研究中，我们报告的新形式的AR改变是普遍的HRPC。通过计算机序列分析和随后的实验验证研究，我们发现了7个AR变体转录本缺乏配体结合结构域的阅读框架，这是由于“内含子”隐蔽外显子剪接到编码AR DNA结合结构域的上游外显子。我们专注于两种表达最丰富的变体AR-V1和AR-V7，以进行更详细的分析。AR-V1和AR-V7 mRNA在HRPC（n=25）中的表达平均比激素初治PCa（n=82）高20倍（p<0.0001）。在激素初治PCa中，AR-V7的高表达预测了手术治疗后的生化复发（p=0.012）。AR-V7特异性多克隆抗体在HRPC标本中经常检测到AR-V7蛋白，但在激素初治PCa标本中很少检测到。AR-V7定位于雄激素耗竭条件下培养的PCa细胞的细胞核中，并且在驱动典型雄激素应答基因的表达方面具有组成性活性，如AR报告基因测定和表达微阵列分析所揭示的。这些结果表明，HRPC的发展，值得进一步研究的新机制。此外，作为致死性PCa的表达标志物，这些新的AR变体可被探索为晚期PCa的潜在生物标志物和治疗靶点。
Suppression of androgen production and function provides palliation but not cure in men with prostate cancer (PCa). Therapeutic failure and progression to hormone refractory prostate cancer (HRPC) are often accompanied by molecular alterations involving the androgen receptor (AR). In this study, we report novel forms of AR alteration that are prevalent in HRPC. Through in silico sequence analysis and subsequent experimental validation studies, we uncovered 7 AR variant transcripts lacking the reading frames for the ligand-binding domain, due to splicing of “intronic” cryptic exons to the upstream exons encoding the AR DNA binding domain. We focused on the two most abundantly expressed variants, AR-V1, and AR-V7, for more detailed analysis. AR-V1 and AR-V7 mRNA demonstrated an average 20-fold higher expression in HRPC (n=25) when compared to hormone naïve PCa (n=82) (p<0.0001). Among the hormone naïve PCa, higher expression of AR-V7 predicted biochemical recurrence following surgical treatment (p=0.012). Polyclonal antibodies specific to AR-V7 detected the AR-V7 protein frequently in HRPC specimens but rarely in hormone naïve PCa specimens. AR-V7 was localized in the nuclei of cultured PCa cells under androgen-depleted conditions, and constitutively active in driving the expression of canonical androgen responsive genes, as revealed by both AR reporter assays and expression microarray analysis. These results suggest a novel mechanism for the development of HRPC that warrants further investigation. In addition, as expression markers for lethal PCa, these novel AR variants may be explored as potential biomarkers and therapeutic targets for advanced PCa.