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Cancer Cell International
Published in: Cancer Cell International 1/2018

Open Access 01-12-2018 | Primary research

MiR-98 modulates macrophage polarization and suppresses the effects of tumor-associated macrophages on promoting invasion and epithelial–mesenchymal transition of hepatocellular carcinoma

Authors: Lei Li, Pengfei Sun, Chengsheng Zhang, Zongchao Li, Kai Cui, Wuyuan Zhou

Published in: Cancer Cell International | Issue 1/2018

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Abstract

Background

Tumor-associated macrophages (TAMs) are generally recognized as a promoter of tumor progression. miR-98 has been shown to suppress the proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells. Here, we aim to investigate the role of miR-98-mediated macrophage polarization in HCC progression.

Methods

Human blood monocytes were isolated from healthy male donors and incubated with culture medium collected from HepG2 cells for 7 days. The phenotype of the macrophages was detected. The protein expression was detected by Western blot. Levels of cytokines secreted in culture medium were measured using the specific enzyme-linked immunosorbent assay kits. To explore the role of miR-98 in HCC-conditioned TAMs, HCC cells HepG2 and SMMC7721 were cultured with conditioned medium from HCC-conditioned TAMs that had been transfected with miR-98 mimic/inhibitor. Cell proliferation, migration and invasion assays were performed.

Results

HCC-conditioned TAMs possessed M2-like phenotype, including increased protein expression of CD163 and TNF-αlow, IL-1βlow, TGF-βhigh and IL-10high phenotype. HCC-conditioned TAMs also promoted proliferation, migration, invasion and EMT of HepG2 and SMMC7721 cells. Furthermore, miR-98 modulated macrophage polarization from M2 to M1 in HCC-conditioned TAMs, as evidenced by the alteration of M1- or M2-related cytokines. Moreover, miR-98 mimic significantly suppressed the HCC-conditioned TAMs-mediated promotion of cell migration, invasion and EMT in HepG2 and SMMC7721 cells compared with negative control, whereas miR-98 inhibitor exerted reversed effects.

Conclusions

miR-98 may play a vital role in regulating macrophage polarization, thereby suppressing the TAMs-mediated promotion of invasion and EMT in HCC.
Appendix
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Literature
1.
Siegel RL, Fedewa SA, Miller KD, Goding-Sauer A, Pinheiro PS, Martinez-Tyson D, Jemal A. Cancer statistics for Hispanics/Latinos, 2015. Ca A Cancer J Clin. 2012;65(5):283–98.CrossRef
2.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortettieulent J, Jemal A. Global cancer statistics, 2012. Ca A Cancer J Clin. 2015;65(2):87.CrossRef
3.
Wang Z, Lu X, Hu Y, Huang Y, Zhang Y, Zheng X, Wang S, Wang Y, Yu Y, Meng Z. miRNA let-7b modulates macrophage polarization and enhances tumor-associated macrophages to promote angiogenesis and mobility in prostate cancer. Sci Rep. 2016;6:25602.CrossRefPubMedPubMedCentral
4.
Capece D, Fischietti M, Verzella D, Gaggiano A, Cicciarelli G, Tessitore A, Zazzeroni F, Alesse E. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int. 2012;2013(1):187204.PubMedPubMedCentral
5.
Mcwhorter FY, Davis CT, Liu WF. Physical and mechanical regulation of macrophage phenotype and function. Cell Mol Life Sci. 2015;72(7):1303.CrossRefPubMed
6.
Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010;22(2):231–7.CrossRefPubMed
7.
8.
Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer. 2006;42(6):717–27.CrossRefPubMed
9.
Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, Zammataro L, Pasqualini F, Nebuloni M, Chiabrando C, Mantovani A. Tumor-Conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J Immunol. 2010;185(1):642–52.CrossRefPubMed
10.
Takayama H, Nishimura K, Tsujimura A, Nakai Y, Nakayama M, Aozasa K, Okuyama A, Nonomura N. Increased infiltration of tumor associated macrophages is associated with poor prognosis of bladder carcinoma in situ after intravesical bacillus Calmette-Guerin instillation. J Urol. 2009;179(4):1894–900.CrossRef
11.
Bacman D, Merkel S, Croner R, Papadopoulos T, Brueckl W, Dimmler A. TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study. BMC Cancer. 2007;7(1):156.CrossRefPubMedPubMedCentral
12.
Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, Wu WZ, Wang L, Tang ZY, Sun HC. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26(16):2707–16.CrossRefPubMed
13.
Rizos E, Siafakas N, Katsantoni E, Skourti E, Salpeas V, Rizos I, Tsoporis JN, Kastania A, Filippopoulou A, Xiros N, et al. Let-7, mir-98 and mir-183 as biomarkers for cancer and schizophrenia [corrected]. PLoS ONE. 2015;10(4):e0123522.CrossRefPubMedPubMedCentral
14.
Wendler A, Keller D, Albrecht C, Peluso JJ, Wehling M. Involvement of let-7/miR-98 microRNAs in the regulation of progesterone receptor membrane component 1 expression in ovarian cancer cells. Oncol Rep. 2011;25(1):273–9.PubMed
15.
Zhang JJ, Chen JT, Hua L, Yao KH, Wang CY. miR-98 inhibits hepatocellular carcinoma cell proliferation via targeting EZH2 and suppressing Wnt/beta-catenin signaling pathway. Biomed Pharmacother. 2017;85:472–8.CrossRefPubMed
16.
Wang YC, Chen YL, Yuan RH, Pan HW, Yang WC, Hsu HC, Jeng YM. Lin-28B expression promotes transformation and invasion in human hepatocellular carcinoma. Carcinogenesis. 2010;31(9):1516–22.CrossRefPubMed
17.
Zhou W, Zou B, Liu L, Cui K, Gao J, Yuan S, Cong N. MicroRNA-98 acts as a tumor suppressor in hepatocellular carcinoma via targeting SALL4. Oncotarget. 2016;7(45):74059–73.PubMedPubMedCentral
18.
Kaczmarek M, Nowicka A, Kozlowska M, Zurawski J, Batura-Gabryel H, Sikora J. Evaluation of the phenotype pattern of macrophages isolated from malignant and non-malignant pleural effusions. Tumour Biol. 2011;32(6):1123–32.CrossRefPubMed
19.
Sakai Y, Honda M, Fujinaga H, Tatsumi I, Mizukoshi E, Nakamoto Y, Kaneko S. Common transcriptional signature of tumor-infiltrating mononuclear inflammatory cells and peripheral blood mononuclear cells in hepatocellular carcinoma patients. Cancer Res. 2008;68(24):10267–79.CrossRefPubMed
20.
Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, Kammula US, Chen Y, Qin LX, Tang ZY. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006;10(2):99.CrossRefPubMed
21.
Li YW, Qiu SJ, Fan J, Gao Q, Zhou J, Xiao YS, Xu Y, Wang XY, Sun J, Huang XW. Tumor-infiltrating macrophages can predict favorable prognosis in hepatocellular carcinoma after resection. J Cancer Res Clin Oncol. 2009;135(3):439.CrossRefPubMed
22.
Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, Loh M, Bolze A, Quek R, Lee VK. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol. 2010;52(3):370.CrossRefPubMed
23.
Chaudhuri AA, So AY, Sinha N, Gibson WS, Taganov KD, O’Connell RM, Baltimore D. MicroRNA-125b potentiates macrophage activation. J Immunol. 2011;187(10):5062–8.CrossRefPubMedPubMedCentral
24.
Androulidaki A, Iliopoulos D, Arranz A, Doxaki C, Schworer S, Zacharioudaki V, Margioris AN, Tsichlis PN, Tsatsanis C. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity. 2009;31(2):220.CrossRefPubMedPubMedCentral
25.
Kumar M, Sahu SK, Kumar R, Subuddhi A, Maji RK, Jana K, Gupta P, Raffetseder J, Lerm M, Ghosh Z. MicroRNA let-7 Modulates the immune response to Mycobacterium tuberculosis infection via control of A20, an inhibitor of the NF-κB pathway. Cell Host Microb. 2015;17(3):345–56.CrossRef
26.
Yu D, Yang L, Lv H, Zhou S, Zhen S, Min W. miR-98 suppresses tumor cell growth and metastasis by targeting IGF1R in oral squamous cell carcinoma. Int J Clin Exp Pathol. 2015;8(10):12252.
27.
Ran N, Huang Y, Jing W. miR-98 targets ITGB3 to inhibit proliferation, migration, and invasion of non-small-cell lung cancer. Oncotargets Ther. 2015;8(default):2689–97.
28.
Li F, Li X, Qiao L, Shi F, Liu W, Li Y, Dang Y, Gu W, Wang X, Liu W. miR-98 suppresses melanoma metastasis through a negative feedback loop with its target gene IL-6. Exp Mol Med. 2014;46(10):e116.CrossRefPubMedPubMedCentral
29.
Fan YH, Ye MH, Wu L, Lv SG, Wu MJ, Xiao B, Liao CC, Ji QK, Chai Y, Zhu XG. Overexpression of miR-98 inhibits cell invasion in glioma cell lines via downregulation of IKKε. Eur Rev Med Pharmacol Sci. 2015;19(19):3593.PubMed
30.
Lin X, Chen L, Yao Y, Zhao R, Cui X, Chen J, Hou K, Zhang M, Su F, Chen J, et al. CCL18-mediated down-regulation of miR98 and miR27b promotes breast cancer metastasis. Oncotarget. 2015;6(24):20485–99.PubMedPubMedCentral
31.
Shin HD, Park BL, Kim LH, Jung JH, Kim JY, Yoon JH, Kim YJ, Lee HS. Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma. Hum Mol Genet. 2003;12(8):901–6.CrossRefPubMed
Metadata
Title
MiR-98 modulates macrophage polarization and suppresses the effects of tumor-associated macrophages on promoting invasion and epithelial–mesenchymal transition of hepatocellular carcinoma
Authors
Lei Li
Pengfei Sun
Chengsheng Zhang
Zongchao Li
Kai Cui
Wuyuan Zhou
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2018
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-018-0590-3

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