PAGE4 positivity is associated with attenuated AR signaling and predicts patient survival in hormone-naive prostate cancer.
PAGE4 positivity is associated with attenuated AR signaling and predicts patient survival in hormone-naive prostate cancer.
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DOI：
10.1016/j.ajpath.2012.06.040
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发表时间：
2012-10
期刊：
影响因子：
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通讯作者：
N. Sampson;C. Ruiz;C. Zenzmaier;L. Bubendorf;P. Berger
中科院分区：
文献类型：
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作者：
N. Sampson;C. Ruiz;C. Zenzmaier;L. Bubendorf;P. Berger
雄激素受体（AR）的异常激活在前列腺癌（PCa）发生和发展为去势抵抗性前列腺癌（CR-PCa）的过程中起着关键作用，雄激素剥夺治疗是前列腺癌的主要全身治疗方法。消除AR活性和预测侵袭性肿瘤行为的生物标志物的新策略对于改善治疗干预至关重要。前列腺癌组织微阵列显示，前列腺相关基因4 (PAGE4)，一种x链癌/睾丸抗原，在癌前病变的上皮中与良性上皮相比高度上调，但随后随着肿瘤进展而降低。我们发现，在体外和体内表达page4的细胞中，AR信号被减弱，这很可能是由于雄激素诱导的AR核易位受损，随后降低了AR蛋白的稳定性和丝氨酸81和213的磷酸化。在激素初始和CR-PCa临床标本中，上皮PAGE4蛋白水平与AR激活状态一致呈负相关。此外，PAGE4损害了CR-PCa异种移植的发展，强PAGE4免疫反应性独立预测了激素初始PCa患者的良好生存。总的来说，这些数据表明上皮细胞PAGE4的失调调节AR信号，从而促进晚期致死性PCa的进展，并突出了PAGE4作为预后和治疗靶点的潜在价值。
Aberrant activation of the androgen receptor (AR) plays a key role during prostate cancer (PCa) development and progression to castration-resistant prostate cancer (CR-PCa) after androgen deprivation therapy, the mainstay systemic treatment for PCa. New strategies to abrogate AR activity and biomarkers that predict aggressive tumor behavior are essential for improved therapeutic intervention. PCa tissue microarrays herein reveal that prostate-associated gene 4 (PAGE4), an X-linked cancer/testis antigen, is highly up-regulated in the epithelium of preneoplastic lesions compared with benign epithelium, but subsequently decreases with tumor progression. We show that AR signaling is attenuated in PAGE4-expressing cells bothin vitroandin vivo, most likely via impaired androgen-induced AR nuclear translocation and subsequently reduced AR protein stabilization and phosphorylation at serines 81 and 213. Consistently, epithelial PAGE4 protein levels inversely correlated with AR activation status in hormone-naive and CR-PCa clinical specimens. Moreover, PAGE4 impaired the development of CR-PCa xenografts, and strong PAGE4 immunoreactivity independently predicted favorable patient survival in hormone-naive PCa. Collectively, these data suggest that dysregulation of epithelial PAGE4 modulates AR signaling, thereby promoting progression to advanced lethal PCa and highlight the potential value of PAGE4 as a prognostic and therapeutic target.