A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance.
A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance.
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DOI：
10.1016/j.molcel.2016.11.034
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发表时间：
2017-01-05
期刊：
影响因子：
16
通讯作者：
Luo JL
中科院分区：
文献类型：
--
作者：
Jeong JH;Park SJ;Dickinson SI;Luo JL
雄激素剥夺治疗是晚期前列腺癌最有效的治疗方法，然而，几乎所有的癌症最终都会变得去势抵抗，其潜在机制在很大程度上尚不清楚。在此，我们发现在去势抵抗性前列腺癌（CRPC）的出现过程中，形成了由IκBα/NF-κB（p65）、miR-196 B-3 p、Meis 2、PPP 3CC组成的内在组成性激活的前馈信号通路。该回路控制干细胞转录因子的表达，从而驱动CRPC细胞的高致瘤性。通过靶向其单个组分来中断回路显著损害致瘤性和CRPC发展。值得注意的是，该回路中IκBα/NF-κB（p65）的组成性激活不依赖于在正常免疫应答中重要的传统IKKβ/NF-κB途径的激活。因此，我们的研究对去势抵抗的真正机制提出了深刻的见解，并为CRPC治疗策略的开发提供了基础，这些治疗策略将是高效的，同时避免在正常细胞中不加选择地抑制IKK/NF-κB。
Androgen deprivation therapy is the most effective treatment for advanced prostate cancer, however, almost all cancer eventually become castration-resistant, and the underlying mechanisms are largely unknown. Here, we show that an intrinsic constitutively activated feed-forward signaling circuit composed of IκBα/NF-κB(p65), miR-196b-3p, Meis2, PPP3CC is formed during the emergence of castration-resistant prostate cancer (CRPC). This circuit controls the expression of stem cell transcription factors that drives the high tumorigenicity of CRPC cells. Interrupting the circuit by targeting its individual components significantly impairs the tumorigenicity and CRPC development. Notably, constitutive activation of IκBα/NF-κB(p65) in this circuit is not dependent on the activation of traditional IKKβ/NF-κB pathways that are important in normal immune responses. Therefore, our studies present deep insight into the bona fide mechanisms underlying castration-resistance and provide the foundation for the development of CRPC therapeutic strategies that would be highly efficient while avoiding indiscriminate IKK/NF-κB inhibition in normal cells.