Targeting the androgen receptor with siRNA promotes prostate cancer metastasis through enhanced macrophage recruitment via CCL2/CCR2-induced STAT3 activation.
Targeting the androgen receptor with siRNA promotes prostate cancer metastasis through enhanced macrophage recruitment via CCL2/CCR2-induced STAT3 activation.
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DOI：
10.1002/emmm.201202367
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发表时间：
2013-09
影响因子：
11.1
通讯作者：
Chang C
中科院分区：
文献类型：
--
作者：
Izumi K;Fang LY;Mizokami A;Namiki M;Li L;Lin WJ;Chang C
前列腺癌（PCa）细胞中CCL 2表达增加通过巨噬细胞募集增强转移。然而，其与雄激素受体（AR）介导的PCa进展的联系仍不清楚。在这里，我们确定了一个以前未被认识到的调节：在PCa细胞中用siRNA靶向AR通过CCL 2上调增加巨噬细胞募集，这可能导致增强PCa侵袭力。分子机制分析表明，siRNA靶向PCa AR可通过CCL 2依赖的STAT 3激活和上皮-间质转化（EMT）途径促进PCa细胞迁移/侵袭。重要的是，CCL 2/CCR 2-STAT 3轴的药理学中断抑制EMT和PCa细胞迁移，提供了一种连接CCL 2和EMT的新机制。用siRNA和CCL 2/CCR 2-STAT 3轴同时靶向PCa AR导致异种移植物PCa小鼠模型中PCa生长和转移的更好抑制。人类前列腺癌组织芯片分析表明，增加CCL 2表达可能与前列腺癌患者的预后不良。总之，这些结果可以提供一种新的治疗方法，通过靶向AR与siRNA和抗CCL 2/CCR 2-STAT 3信号传导的组合，在去势抵抗阶段更好地对抗PCa进展和转移。
Increased CCL2 expression in prostate cancer (PCa) cells enhanced metastasis via macrophage recruitment. However, its linkage to androgen receptor (AR)-mediated PCa progression remains unclear. Here, we identified a previously unrecognized regulation: targeting AR with siRNA in PCa cells increased macrophage recruitment via CCL2 up-regulation, which might then result in enhancing PCa invasiveness. Molecular mechanism dissection revealed that targeting PCa AR with siRNA promoted PCa cell migration/invasion via CCL2-dependent STAT3 activation and epithelial–mesenchymal transition (EMT) pathways. Importantly, pharmacologic interruption of the CCL2/CCR2-STAT3 axis suppressed EMT and PCa cell migration, providing a new mechanism linking CCL2 and EMT. Simultaneously targeting PCa AR with siRNA and the CCL2/CCR2-STAT3 axis resulted in better suppression of PCa growth and metastasis in a xenograft PCa mouse model. Human PCa tissue microarray analysis suggests that increased CCL2 expression may be potentially associated with poor prognosis of PCa patients. Together, these results may provide a novel therapeutic approach to better battle PCa progression and metastasis at the castration resistant stage via the combination of targeting AR with siRNA and anti-CCL2/CCR2-STAT3 signalling.
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影响因子：
8
作者：
Kaler, P.;Augenlicht, L.;Klampfer, L.
通讯作者：
Klampfer, L.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Loberg, Robert D.;Ying, Chi;Pienta, Kenneth J.
通讯作者：
Pienta, Kenneth J.
影响因子：
50.3
作者：
Mulholland DJ;Tran LM;Li Y;Cai H;Morim A;Wang S;Plaisier S;Garraway IP;Huang J;Graeber TG;Wu H
通讯作者：
Wu H
影响因子：
50.3
作者：
Carver BS;Chapinski C;Wongvipat J;Hieronymus H;Chen Y;Chandarlapaty S;Arora VK;Le C;Koutcher J;Scher H;Scardino PT;Rosen N;Sawyers CL
通讯作者：
Sawyers CL