Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages
Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages
复制标题
强制激活巨噬细胞中的 Notch 通过上调 miR-125a 和禁用肿瘤相关巨噬细胞来抑制肿瘤生长
DOI：
10.1158/0008-5472.can-15-2019
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发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Qin, Hong-Yan
中科院分区：
文献类型：
--
作者：
Zhao, Jun-Long;Huang, Fei;Qin, Hong-Yan
肿瘤相关巨噬细胞（TAM）对癌症的标志有很大贡献。Notch阻断被证明可以阻止TAM分化，但确切的作用和潜在的机制需要阐明。在这项研究中，我们采用了一种转基因小鼠模型，其中Notch 1细胞内结构域（NIC）被有条件地激活，以确定激活Notch 1信号转导在巨噬细胞中的作用。NIC过表达对TAM分化没有影响，但它废除了TAM功能，导致移植肿瘤的生长抑制。巨噬细胞miRNA谱鉴定了Notch信号传导的新型下游介质miR-125 a，其通过宿主基因Spaca 6A的第一内含子增强子处的RBP-J结合位点上调。miR-125 a在Notch信号下游发挥作用，分别通过调节抑制缺氧诱导因子-1 α和IRF 4的因子来影响M1和M2巨噬细胞的极化。值得注意的是，用miR-125 a模拟物转染的巨噬细胞通过重塑免疫微环境来增加吞噬活性并抑制肿瘤生长。我们还鉴定了RYBP和YY 1介导的miR-125 a表达的正反馈环。总之，我们的结果表明，Notch信号不仅支持TAM的分化，而且通过miR-125 a拮抗其促肿瘤功能。靶向这种miRNA可以重新编程肿瘤微环境中的巨噬细胞并恢复其抗肿瘤潜力。(C)2016年AACR。
Tumor-associated macrophages (TAM) contribute greatly to hallmarks of cancer. Notch blockade was shown to arrest TAM differentiation, but the precise role and underlying mechanisms require elucidation. In this study, we employed a transgenic mouse model in which the Notch1 intracellular domain (NIC) is activated conditionally to define the effects of active Notch1 signaling in macrophages. NIC overexpression had no effect on TAM differentiation, but it abrogated TAM function, leading to repressed growth of transplanted tumors. Macrophage miRNA profiling identified a novel downstream mediator of Notch signaling, miR-125a, which was upregulated through an RBP-J-binding site at the first intronic enhancer of the host gene Spaca6A. miR-125a functioned downstream of Notch signaling to reciprocally influence polarization of M1 and M2 macrophages by regulating factor inhibiting hypoxia inducible factor-1 alpha and IRF4, respectively. Notably, macrophages transfected with miR-125a mimetics increased phagocytic activity and repressed tumor growth by remodeling the immune microenvironment. We also identified a positive feedback loop for miR-125a expression mediated by RYBP and YY1. Taken together, our results showed that Notch signaling not only supported the differentiation of TAM but also antagonized their protumorigenic function through miR-125a. Targeting this miRNA may reprogram macrophages in the tumor microenvironment and restore their antitumor potential. (C) 2016 AACR.