A double feedback loop mediated by microRNA-23a/27a/24-2 regulates M1 versus M2 macrophage polarization and thus regulates cancer progression

// Sisi Ma 1 , Min Liu 1 , Zhenbiao Xu 1 , Yanshuang Li 1 , Hui Guo 1 , Yehua Ge 1 , Yanxin Liu 1 , Dexian Zheng 1 and Juan Shi 1 1 National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China Correspondence to: Juan Shi, email: // Dexian Zheng, email: // Keywords : tumor associated macrophage; miRNA; macrophage polarization; tumor therapy; tumor microenvironment Received : April 24, 2015 Accepted : October 23, 2015 Published : November 02, 2015 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.