Testicular orphan nuclear receptor 4 is associated with the radio-sensitivity of prostate cancer
Testicular orphan nuclear receptor 4 is associated with the radio-sensitivity of prostate cancer
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睾丸孤儿核受体4与前列腺癌的放射敏感性相关
DOI：
10.1002/pros.23044
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发表时间：
2015
期刊：
影响因子：
2.8
通讯作者：
Chang Chawnshang
中科院分区：
文献类型：
--
作者：
Yu Shicheng;Wang Mingchao;Ding Xianfan;Xia Liqun;Chen Bide;Chen Yicheng;Zhang Zhigen;Niu Yuanjie;Li Gonghui;Chang Chawnshang
研究背景众所周知，相当数量的前列腺癌（PCa）表现出不同程度的放射抵抗，治疗后肿瘤可能复发。最近的研究表明，睾丸孤儿核受体4（TR 4）可以在抗氧化应激反应中发挥关键作用，并可能调节DNA损伤修复。本研究的目的是探讨TR 4在PCa放疗中的作用。方法采用免疫组化（IHC）法检测PCa患者近距离放疗后组织标本中TR 4的表达。采用细胞存活试验和集落形成试验检测TR 4基因表达调控的PCa细胞对照射的敏感性，发现近距离放射治疗后生化复发（BCR）的复发性TSPCa患者TR 4表达（80%，n = 30）明显高于无BCR患者（36.67%，n = 30）。生存分析显示，TR 4高表达患者的BCR发生率显著高于低表达患者（HR = 3.474，95%CI 1.678- 7.192，P = 0.0008）。多因素分析显示，RT-4染色评分是预测PCa患者放疗后临床预后的唯一有意义的变量（OR = 9.919，95%CI 2.516- 39.101，P = 0.001）。使用细胞存活试验和集落形成试验，我们发现在PC 3细胞中添加功能性TR 4导致放射抗性升高。相反，在LNCaP细胞中敲低TR 4导致放射敏感性增加。结论TR 4可介导PCa细胞的放射敏感性，可作为PCa放疗患者的预后指标。这项研究提供了一种新的方法来操纵PCa细胞的放射敏感性，并可能在未来带来放射治疗的促进治疗结果，以对抗PCa.Prostate 75：1632-1642，2015。© 2015威利期刊公司.
BACKGROUNDIt is well known that a significant number of prostate cancers (PCa) showed different extents of radio‐resistance and the tumor may recur after treatment. Recent studies demonstrated that Testicular orphan nuclear receptor 4 (TR4) could play a critical role in anti‐oxidative stress responses and might modulate the DNA damage repair. The objective of this study is to investigate the role of TR4 in the radiotherapy for PCa.METHODSThe TR4 expression in tissue samples from PCa patients treated with brachytherapy was measured by immunohistochemistry (IHC). Cell survival test and colony formation assay were applied to test the radio‐sensitivity of PCa cells with modulated TR4 gene expression upon irradiation.RESULTSPCa patients with biochemical recurrence (BCR) after brachytherapy tend to have higher TR4 expression (80%, n = 30) as compared to those without BCR (36.67%, n = 30). Survival analysis demonstrated a significant higher BCR occurrence in patients with high level of TR4 expression (HR = 3.474, 95%CI 1.678–7.192,P= 0.0008). Multivariate analysis showed that the TR4 staining score on IHC was the only significant variable for predicting the PCa patients' clinical outcomes after radiotherapy (OR = 9.919, 95% CI 2.516–39.101,P= 0.001). Using cell survival test and colony forming assay, we found that the addition of functional TR4 in PC3 cells lead to elevated radio‐resistance. In contrast, knocking‐down TR4 in LNCaP cells resulted in increased radio‐sensitivity. TheγH2AX foci kinetic analysis suggested that knocking down TR4 might delay the PCa cell's DNA damage repair which would enhance the radio‐sensitivity.CONCLUSIONTR4 could mediate the PCa cells' radio‐sensitivity and might become a prognostic indicator for PCa patients received radiotherapy. This study provides a novel approach to manipulate radio‐sensitivity of PCa cells, and may bring a promoted therapeutic outcome of radiotherapy to battle PCa in future.Prostate 75:1632–1642, 2015. © 2015 Wiley Periodicals, Inc.