INT-HA induces M2-like macrophage differentiation of human monocytes via TLR4-miR-935 pathway

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2019-02, Vol.68 (2), p.189-200
• Main Authors: Zhang, Boke, Du, Yan, He, Yiqing, Liu, Yiwen, Zhang, Guoliang, Yang, Cuixia, Gao, Feng
• Format: Article
• Language: English
• Subjects: Adult; Cancer Research; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Differentiation - immunology; Cells, Cultured; Female; Gene Expression Profiling; Genotype & phenotype; Humans; Hyaluronic acid; Hyaluronic Acid - chemistry; Hyaluronic Acid - metabolism; Hyaluronic Acid - pharmacology; Immunology; Macrophage Activation - drug effects; Macrophage Activation - immunology; Macrophages; Macrophages - classification; Macrophages - immunology; Macrophages - metabolism; Male; Medicine; Medicine & Public Health; MicroRNAs - genetics; MicroRNAs - immunology; Middle Aged; miRNA; Molecular Weight; Monocytes; Monocytes - immunology; Monocytes - metabolism; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Oncology; Original; Original Article; Peripheral blood; Phenotypes; Polarization; Signal Transduction - genetics; Signal Transduction - immunology; Solid tumors; Therapeutic applications; THP-1 Cells; TLR4 protein; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Tumors
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-018-2261-6

As a major component of the microenvironment of solid tumors, tumor-associated macrophages (TAMs) facilitate tumor progression. Intermediate-sized hyaluronan (INT-HA) fragments have an immunological function in cell differentiation; however, their role in promoting the polarization of non-activated macrophages to an M2-like TAM phenotype has not been characterized, and the underlying mechanisms remain unclear. Here, we used a miRNA microarray to find that some miRNAs (especially miR-935) were differentially regulated in INT-HA-induced M2-like macrophages. According to RT-qPCR and Western blot, there was an association between miR-935 and C/EBPβ, that control the polarization of macrophages. Moreover, we found that INT-HA induced an M2-like phenotype via the TLR4 receptor. In our study, there was a negative correlation between plasma HA and miR-935 in monocytes from the peripheral blood of patients with solid tumors. There was also a negative correlation between miR-935 and M2-like macrophage markers in monocytes. These findings suggest that HA fragments interact with TLR4 and educate macrophage polarization to an M2-like phenotype via miR-935. Therefore, this study provides new insight into the role of miR-935 in INT-HA-induced M2-like polarization, and suggests a potential therapeutic target for antitumor treatment.