Cancer Immunology, Immunotherapy

, Volume 68, Issue 2, pp 189–200 | Cite as

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

  • Boke Zhang
  • Yan Du
  • Yiqing He
  • Yiwen Liu
  • Guoliang Zhang
  • Cuixia Yang
  • Feng GaoEmail author
Original Article


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.


Hyaluronan MiR-935 TLR4 CD44 Tumor-associated macrophage 



Arginase 1


Blank control


Extracellular matrix


Glyceraldehyde 3-phosphate dehydrogenase




High molecular weight hyaluronan




Intermediate-sized hyaluronan


Low molecular weight hyaluronan




Negative control


Quantitative PCR with reverse transcription


Tumor-associated macrophages


Toll-like receptor 4


Authors’ contributions

BZ, YD, and FG contributed to the conception, design, and final approval of the submitted version. YH and YL performed the research and collected data. BZ, CY, and YD analyzed the data. BZ, GZ, and FG wrote and revised the manuscript. All authors read and approved the final manuscript.


This study was supported by the National Natural Science Foundation of China (81702852, 81572821, 81502491, 81502490, and 81672843), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20171924), the Program of Shanghai Leading Talents (2013-038), and the Yuyan Program of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (LYZY-0245).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval and ethical standards

This study was performed according to the revised Declaration of Helsinki, 2013. All related human subject procedures were approved by the Ethics Committee of Shanghai Jiao Tong University (approval number: YS-2017-41). Peripheral blood samples were obtained from the Shanghai Jiao Tong University Affiliated Sixth People’s Hospital.

Informed consent

Informed consents were obtained from all participants in the study.

Supplementary material

262_2018_2261_MOESM1_ESM.pdf (469 kb)
Supplementary material 1 (PDF 468 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Boke Zhang
    • 1
  • Yan Du
    • 1
  • Yiqing He
    • 1
  • Yiwen Liu
    • 1
  • Guoliang Zhang
    • 1
  • Cuixia Yang
    • 1
  • Feng Gao
    • 2
    Email author
  1. 1.Department of Molecular BiologyShanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghaiPeople’s Republic of China
  2. 2.Department of Molecular Biology and Clinical LaboratoryShanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghaiPeople’s Republic of China

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