title: Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages.
abstract: 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.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Jun-Long
authors.initials: JL
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Hepatic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Fei
authors.initials: F
authors.lastname: He
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Chun-Chen
authors.initials: CC
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Shi-Qian
authors.initials: SQ
authors.lastname: Liang
authors.affiliation: Department of Hepatic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Guang-Ying
authors.initials: GY
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China. Department of Hepatic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China. hyqin@fmmu.edu.cn huahan@fmmu.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Han
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China. hyqin@fmmu.edu.cn huahan@fmmu.edu.cn.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Qin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*; D050986:YY1 Transcription Factor / Q000235:genetics; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D035683:MicroRNAs; D051881:Receptor, Notch1; D012097:Repressor Proteins; D050986:YY1 Transcription Factor; D000099218:Interferon Regulatory Factor-4; C527468:Mirn125 microRNA, mouse; C497762:Notch1 protein, mouse; C120616:Rybp protein, mouse; C494699:Yy1 protein, mouse