Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages
| Autor: | Chun-Chen Gao, Jun-Long Zhao, Guang-Ying Dong, Peng-Fei Ma, Fei Huang, Shi-Qian Liang, Fei He, Hong-Yan Qin, Hua Han |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Cellular differentiation Notch signaling pathway Mice Transgenic Biology Cell Line Mice 03 medical and health sciences 0302 clinical medicine Animals Macrophage Receptor Notch1 YY1 Transcription Factor Regulation of gene expression Tumor microenvironment Macrophages Cell Differentiation Up-Regulation Cell biology Gene Expression Regulation Neoplastic Mice Inbred C57BL Repressor Proteins MicroRNAs 030104 developmental biology Oncology 030220 oncology & carcinogenesis Interferon Regulatory Factors Immunology Signal transduction Signal Transduction IRF4 Interferon regulatory factors |
| Zdroj: | Cancer Research. 76:1403-1415 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-15-2019 |
| Popis: | 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-1α 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. Cancer Res; 76(6); 1403–15. ©2016 AACR. |
| Databáze: | OpenAIRE |
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