title: A double feedback loop mediated by microRNA-23a/27a/24-2 regulates M1 versus M2 macrophage polarization and thus regulates cancer progression.
abstract: In response to microenvironmental signals, macrophages undergo different types of activation, including the "classic" pro-inflammatory phenotype (also called M1) and the "alternative" anti-inflammatory phenotype (also called M2). Macrophage polarized activation has profound effects on immune and inflammatory responses, but mechanisms underlying the various types of macrophage is still in its infancy. In this study, we reported that M1-type stimulation could down-regulate miR-23a/27a/24-2 cluster transcription through the binding of NF-κB to this cluster's promoter and that miR-23a in turn activated the NF-κB pathway by targeting A20 and thus promoted the production of pro-inflammatory cytokines. Furthermore, STAT6 occupied the miR-23a/27a/24-2 cluster promoter and activated their transcription in IL-4-stimulated macrophages. In addition, miR-23a in turn suppressed the JAK1/STAT-6 pathway and reduced the production of M2 type cytokines by targeting JAK1 and STAT-6 directly, while miR-27a showed the same phenotype by targeting IRF4 and PPAR-γ. The miR-23a/27a/24-2 cluster was shown to be significantly decreased in TAMs of breast cancer patients, and macrophages overexpressing the miR-23a/27a/24-2 cluster inhibited tumor growth in vivo. Taken together, these data integrated microRNA expression and function into macrophage polarization networks and identified a double feedback loop consisting of the miR-23a/27a/24-2 cluster and the key regulators of the M1 and M2 macrophage polarization pathway. Moreover, miR-23a/27a/24-2 regulates the polarization of tumor-associated macrophages and thus promotes cancer progression.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Sisi
authors.initials: S
authors.lastname: Ma
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Zhenbiao
authors.initials: Z
authors.lastname: Xu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Yanshuang
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Yehua
authors.initials: Y
authors.lastname: Ge
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Dexian
authors.initials: D
authors.lastname: Zheng
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Shi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D018450:Disease Progression; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; C529080:Mirn24 microRNA, mouse; C540674:Mirn27 microRNA, mouse
keywords: macrophage polarization; miRNA; tumor associated macrophage; tumor microenvironment; tumor therapy