TR4 nuclear receptor promotes prostate cancer metastasis via upregulation of CCL2/CCR2 signaling
TR4 nuclear receptor promotes prostate cancer metastasis via upregulation of CCL2/CCR2 signaling
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DOI：
10.1002/ijc.29049
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发表时间：
2015-02-15
影响因子：
6.4
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
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作者：
Ding, Xianfan;Yang, Dong-Rong;Chang, Chawnshang
睾丸核受体4（TR4）对氧化应激和DNA损伤起保护作用，并可能导致衰老。我们最近的临床肿瘤组织染色结果显示，与具有低Gleason评分的组织相比，具有高Gleason评分的前列腺癌（PCa）患者中TR4的表达更高。在体外迁移/侵袭实验中，在PCa细胞中操纵TR4的表达后，显示TR4促进PCa细胞迁移/侵袭。机制解剖发现，CCL2/CCR2信号在TR4促进PCa细胞迁移/侵袭的介导中起关键作用。染色质免疫沉淀和荧光素酶测定进一步证实了TR 4在转录水平上对CCL 2的调节，并且添加CCR2拮抗剂导致TR 4增强的PCa细胞迁移/侵袭的中断。最后，使用表达荧光素酶的CWR22Rv1细胞的原位异种移植小鼠研究发现，TR4增强了PCa转移，并且当将CCR 2拮抗剂注射到小鼠中时，这种增加的转移被逆转。总之，这些体外和体内结果揭示了TR4在PCa转移中的积极作用，并证明了CCL2/CCR2信号传导作为发挥TR4作用的重要介质。这一发现表明，TR4可能代表了与PCa转移相关的生物标志物，靶向TR4-CCL2/CCR2轴可能成为对抗PCa转移的新治疗方法。睾丸核受体4（TR4）对氧化应激和DNA损伤具有保护作用，可能参与衰老。然而，TR4与肿瘤进展的联系仍不清楚。在这里，作者发现了TR4可能与前列腺癌（PCa）Gleason评分相关的第一个临床证据。通过体外研究和体内动物研究，他们表明TR4促进PCa，并证明CCL2/CCR2信号传导是TR4作用的重要介质。研究结果表明，TR4是一个潜在的关键角色，可以用作生物标志物或治疗靶点来对抗PCa转移。
Testicular nuclear receptor 4 (TR4) plays protective roles against oxidative stress and DNA damage and might contribute to aging. Our recent clinical tumor tissue staining results showed higher expression of TR4 in prostate cancer (PCa) patients with high Gleason scores compared to the tissues with the low Gleason scores. In vitro migration/invasion assays after manipulation of the TR4 expression in PCa cells showed that TR4 promoted PCa cells migration/invasion. Mechanism dissection found that the CCL2/CCR2 signal plays the key role in the mediation of TR4-promoted PCa cells migration/invasion. Chromatin immunoprecipitation and Luciferase assays further confirmed TR4 modulation of CCL2 at the transcriptional level and addition of the CCR2 antagonist led to interruption of the TR4-enhanced PCa cells migration/invasion. Finally, the orthotopic xenografted mice studies using the luciferase expressing CWR22Rv1 cells found that TR4 enhanced PCa metastasis and this increased metastasis was reversed when the CCR2 antagonist was injected into the mice. Together, these in vitro and in vivo results revealed a positive role of TR4 in PCa metastasis and demonstrated CCL2/CCR2 signaling as an important mediator in exerting TR4 action. This finding suggests that TR4 may represent a biomarker related to PCa metastasis and targeting the TR4-CCL2/CCR2 axis may become a new therapeutic approach to battle PCa metastasis.What's New? Testicular nuclear receptor 4 (TR4) plays protective roles against oxidative stress and DNA damage and might be involved in aging. The linkage of TR4 to tumor progression, however, remains unclear. Here, the authors found the first clinical evidence that TR4 may be related to the prostate cancer (PCa) Gleason score. Through in vitro studies and in vivo animal studies, they showed that TR4 promotes PCa and also demonstrated CCL2/CCR2 signaling as an important mediator in TR4 action. The findings indicate TR4 as a potential key player that could be used as a biomarker or therapeutic target to battle PCa metastasis.