A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth.
A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth.
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DOI：
10.1158/0008-5472.can-08-3795
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Qiu Y
中科院分区：
文献类型：
--
作者：
Guo Z;Yang X;Sun F;Jiang R;Linn DE;Chen H;Chen H;Kong X;Melamed J;Tepper CG;Kung HJ;Brodie AM;Edwards J;Qiu Y
雄激素受体（AR）在导致无法治愈的雄激素消融抵抗性前列腺癌（PCA）的进展中发挥着关键作用。我们已经在激素不敏感的PCA细胞中鉴定了三种缺乏配体结合结构域的新型AR剪接变体（命名为AR 3、AR 4和AR 5）。AR 3是人前列腺组织中表达的主要剪接变体之一，具有组成型活性，其转录活性不受雄激素或抗雄激素调节。对包含429个人前列腺组织样本的组织微阵列的免疫组织化学分析显示，在PCA进展期间，AR 3显著上调，并且AR 3表达水平与根治性前列腺切除术后肿瘤复发的风险相关。AR 3的过表达赋予PCA细胞的消融非依赖性生长，而在激素抗性PCA细胞中AR 3表达的特异性敲低（不改变AR水平）减弱它们在细胞培养和异种移植模型中在雄激素耗尽条件下的生长，表明AR 3在PCA细胞的消融非依赖性生长中不可或缺的作用。此外，AR 3可能通过调节一组独特的基因（包括AKT1）在消融非依赖性生长中发挥独特而重要的作用，这些基因不受原型AR的调节。我们的数据表明，AR剪接变异体的异常表达可能是PCA进展过程中消融独立性的一种新机制，AR 3可能作为一种预后标志物来预测患者对激素治疗的反应。鉴于这些新的AR剪接变体不受目前可用的抗雄激素药物的抑制，开发靶向这些AR亚型的新药可能对治疗消融抵抗性PCA有效。
The androgen receptor (AR) plays a key role in progression to incurable androgen-ablation resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand binding domain (designated as AR3, AR4 and AR5) in hormone insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly upregulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells while specific knock-down of AR3 expression (without altering AR level) in hormone resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct yet essential role in ablation-independent growth through regulating a unique set of genes including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation-independence during PCA progression and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available anti-androgen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA.