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Abstract: tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and are critical for cancer initiation and progression. microRNAs (miRNAs) could notably influence the phenotype of TAMs through various targets and signal pathways during cancer progression due to their post-transcriptional regulation. In this review, we discuss mainly the regulatory function of miRNAs on macrophage differentiation, functional polarization, and cellular crosstalk. Firstly, during the generation process, miRNAs take part in the differentiation from myeloid cells to mature macrophages, and this maturation process directly influences their recruitment into the TME, attracted by tumor cells. Secondly, macrophages in the TME can be either tumor-promoting or tumor-suppressing, depending on their functional polarization. Large numbers of miRNAs can influence the polarization of macrophages, which is crucial for tumor progression, including tumor cell invasion, intravasation, extravasation, and premetastatic site formation. Thirdly, crosstalk between tumor cells and macrophages is essential for TME formation and tumor progression, and miRNAs can be the mediator of communication in different forms, especially when encapsulated in microvesicles or exosomes. We also assess the potential value of certain macrophage-related miRNAs (MRMs) as diagnostic and prognostic markers, and discuss the possible development of MRM-based therapies.

MicroRNA在肿瘤免疫中的作用:对肿瘤相关巨噬细胞的功能调控

[1]Amin MB, Greene FL, Edge SB, et al., 2017. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin, 67(2):93-99.

[2]Baer C, Squadrito ML, Laoui D, et al., 2016. Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity. Nat Cell Biol, 18(7):790-802.

[3]Bai XZ, Zhang JL, Cao MY, et al., 2018. MicroRNA-146a protects against LPS-induced organ damage by inhibiting Notch1 in macrophage. Int Immunopharmacol, 63:220-226.

[4]Bala S, Marcos M, Kodys K, et al., 2011. Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor α (TNFα) production via increased mRNA half-life in alcoholic liver disease. J Biol Chem, 286(2):1436-1444.

[5]Banerjee S, Xie N, Cui HC, et al., 2013a. MicroRNA let-7c regulates macrophage polarization. J Immunol, 190(12):6542-6549.

[6]Banerjee S, Cui HC, Xie N, et al., 2013b. miR-125a-5p regulates differential activation of macrophages and inflammation. J Biol Chem, 288(49):35428-35436.

[7]Batool A, Wang YQ, Hao XX, et al., 2018. A miR-125b/ CSF1-CX3CL1/tumor-associated macrophage recruitment axis controls testicular germ cell tumor growth. Cell Death Dis, 9(10):962.

[8]Binenbaum Y, Fridman E, Yaari Z, et al., 2018. Transfer of miRNA in macrophage-derived exosomes induces drug resistance in pancreatic adenocarcinoma. Cancer Res, 78(18):5287-5299.

[9]Boldin MP, Taganov KD, Rao DS, et al., 2011. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med, 208(6):1189-1201.

[10]Chafin CB, Regna NL, Caudell DL, et al., 2014. MicroRNA-let-7a promotes E2F-mediated cell proliferation and NFκB activation in vitro. Cell Mol Immunol, 11(1):79-83.

[11]Chai ZT, Zhu XD, Ao JY, et al., 2015. MicroRNA-26a suppresses recruitment of macrophages by down-regulating macrophage colony-stimulating factor expression through the PI3K/Akt pathway in hepatocellular carcinoma. J Hematol Oncol, 8:56.

[12]Challagundla KB, Wise PM, Neviani P, et al., 2015. Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst, 107(7):djv135.

[13]Chaudhuri AA, So AYL, Sinha N, et al., 2011. MicroRNA-125b potentiates macrophage activation. J Immunol, 187(10):5062-5068.

[14]Chen X, Ying X, Wang XJ, et al., 2017. Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. Oncol Rep, 38(1):522-528.

[15]Chen Y, Wang SX, Mu R, et al., 2014. Dysregulation of the miR-324-5p-CUEDC2 axis leads to macrophage dysfunction and is associated with colon cancer. Cell Rep, 7(6):1982-1993.

[16]Cooks T, Pateras IS, Jenkins LM, et al., 2018. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat Commun, 9(1):771.

[17]Cortez-Retamozo V, Etzrodt M, Newton A, et al., 2012. Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci USA, 109(7):2491-2496.

[18]Curtale G, 2018. MiRNAs at the crossroads between innate immunity and cancer: focus on macrophages. Cells, 7(2):12.

[19]Curtale G, Mirolo M, Renzi TA, et al., 2013. Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b. Proc Natl Acad Sci USA, 110(28):11499-11504.

[20]Dean M, Fojo T, Bates S, 2005. Tumour stem cells and drug resistance. Nat Rev Cancer, 5(4):275-284.

[21]el Andaloussi S, Mäger I, Breakefield XO, et al., 2013. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov, 12(5):347-357.

[22]el Gazzar M, Church A, Liu TF, et al., 2011. MicroRNA-146a regulates both transcription silencing and translation disruption of TNF-α during TLR4-induced gene reprogramming. J Leukoc Biol, 90(3):509-519.

[23]Etzrodt M, Cortez-Retamozo V, Newton A, et al., 2012. Regulation of monocyte functional heterogeneity by miR-146a and Relb. Cell Rep, 1(4):317-324.

[24]Fabbri M, Paone A, Calore F, et al., 2012. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci USA, 109(31):E2110-E2116.

[25]Fortunato O, Borzi C, Milione M, et al., 2019. Circulating miR-320a promotes immunosuppressive macrophages M2 phenotype associated with lung cancer risk. Int J Cancer, 144(11):2746-2761.

[26]Frank AC, Ebersberger S, Fink AF, et al., 2019. Apoptotic tumor cell-derived microRNA-375 uses CD36 to alter the tumor-associated macrophage phenotype. Nat Commun, 10(1):1135.

[27]Franklin RA, Liao W, Sarkar A, et al., 2014. The cellular and molecular origin of tumor-associated macrophages. Science, 344(6186):921-925.

[28]Funahashi Y, Kato N, Masuda T, et al., 2019. miR-146a targeted to splenic macrophages prevents sepsis-induced multiple organ injury. Lab Invest, 99(8):1130-1142.

[29]Geissmann F, Manz MG, Jung S, et al., 2010. Development of monocytes, macrophages, and dendritic cells. Science, 327(5966):656-661.

[30]Ghani S, Riemke P, Schönheit J, et al., 2011. Macrophage development from HSCs requires PU.1-coordinated microRNA expression. Blood, 118(8):2275-2284.

[31]Guerriero JL, 2018. Macrophages: the road less traveled, changing anticancer therapy. Trends Mol Med, 24(5):472-489.

[32]Guo J, Liu C, Wang W, et al., 2018. Identification of serum miR-1915-3p and miR-455-3p as biomarkers for breast cancer. PLoS ONE, 13(7):e0200716.

[33]Ha MJ, Kim VN, 2014. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol, 15(8):509-524.

[34]He M, Xu ZQ, Ding T, et al., 2009. MicroRNA-155 regulates inflammatory cytokine production in tumor-associated macrophages via targeting C/EBPβ. Cell Mol Immunol, 6(5):343-352.

[35]Hsieh CH, Tai SK, Yang MH, 2018. Snail-overexpressing cancer cells promote M2-like polarization of tumor-associated macrophages by delivering miR-21-abundant exosomes. Neoplasia, 20(8):775-788.

[36]Hsu YL, Hung JY, Chang WA, et al., 2018. Hypoxic lung-cancer-derived extracellular vesicle microRNA-103a increases the oncogenic effects of macrophages by targeting PTEN. Mol Ther, 26(2):568-581.

[37]Huang F, Zhao JL, Wang L, et al., 2017. miR-148a-3p mediates notch signaling to promote the differentiation and M1 activation of macrophages. Front Immunol, 8:1327.

[38]Ismail N, Wang YJ, Dakhlallah D, et al., 2013. Macrophage microvesicles induce macrophage differentiation and miR-223 transfer. Blood, 121(6):984-995.

[39]Jang JY, Lee JK, Jeon YK, et al., 2013. Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization. BMC Cancer, 13:421.

[40]Kanlikilicer P, Bayraktar R, Denizli M, et al., 2018. Exosomal miRNA confers chemo resistance via targeting Cav1/ p-gp/M2-type macrophage axis in ovarian cancer. EBioMedicine, 38:100-112.

[41]Kumar M, Sahu SK, Kumar R, et al., 2015. MicroRNA let-7 modulates the immune response to Mycobacterium tuberculosis infection via control of A20, an inhibitor of the NF-κB pathway. Cell Host Microbe, 17(3):345-356.

[42]Lan JQ, Sun L, Xu F, et al., 2019. M2 macrophage-derived exosomes promote cell migration and invasion in colon cancer. Cancer Res, 79(1):146-158.

[43]Li D, Duan MY, Feng Y, et al., 2016. MiR-146a modulates macrophage polarization in systemic juvenile idiopathic arthritis by targeting INHBA. Mol Immunol, 77:205-212.

[44]Li L, Sun PF, Zhang CS, et al., 2018. MiR-98 suppresses the effects of tumor-associated macrophages on promoting migration and invasion of hepatocellular carcinoma cells by regulating IL-10. Biochimie, 150:23-30.

[45]Li N, Qin JF, Han X, et al., 2018. miR-21a negatively modulates tumor suppressor genes PTEN and miR-200c and further promotes the transformation of M2 macrophages. Immunol Cell Biol, 96(1):68-80.

[46]Lin L, Lin HB, Wang L, et al., 2015. miR-130a regulates macrophage polarization and is associated with non-small cell lung cancer. Oncol Rep, 34(6):3088-3096.

[47]Lin XB, Wang SY, Sun M, et al., 2019. miR-195-5p/ NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization. J Hematol Oncol, 12(1):20.

[48]Liu JT, Fan LL, Yu HQ, et al., 2019. Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages. Hepatology, 70(1):241-258.

[49]Lu S, Gao Y, Huang XL, et al., 2014. Cantharidin exerts anti-hepatocellular carcinoma by miR-214 modulating macrophage polarization. Int J Biol Sci, 10(4):415-425.

[50]Martinez FO, Gordon S, 2014. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep, 6:13.

[51]Mathsyaraja H, Thies K, Taffany DA, et al., 2015. CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth. Oncogene, 34(28):3651-3661.

[52]Movahedi K, Laoui D, Gysemans C, et al., 2010. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res, 70(14):5728-5739.

[53]Murray PJ, 2017. Macrophage polarization. Annu Rev Physiol, 79:541-566.

[54]Nahid MA, Pauley KM, Satoh M, et al., 2009. miR-146a is critical for endotoxin-induced tolerance: implication in innate immunity. J Biol Chem, 284(50):34590-34599.

[55]Nazari-Jahantigh M, Wei YY, Noels H, et al., 2012. MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. J Clin Invest, 122(11):4190-4202.

[56]Nilsson S, Moller C, Jirström K, et al., 2012. Downregulation of miR-92a is associated with aggressive breast cancer features and increased tumour macrophage infiltration. PLoS ONE, 7(4):e36051.

[57]Noy R, Pollard JW, 2014. Tumor-associated macrophages: from mechanisms to therapy. Immunity, 41(1):49-61.

[58]O'Connell RM, Chaudhuri AA, Rao DS, et al., 2009. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci USA, 106(17):7113-7118.

[59]Ouimet M, Ediriweera HN, Gundra UM, et al., 2015. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest, 125(12):4334-4348.

[60]Parayath NN, Parikh A, Amiji MM, 2018. Repolarization of tumor-associated macrophages in a genetically engineered nonsmall cell lung cancer model by intraperitoneal administration of hyaluronic acid-based nanoparticles encapsulating microRNA-125b. Nano Lett, 18(6):3571-3579.

[61]Park JE, Dutta B, Tse SW, et al., 2019. Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift. Oncogene, 38(26):5158-5173.

[62]Price NL, Rotllan N, Zhang XB, et al., 2019. Specific disruption of abca1 targeting largely mimics the effects of miR-33 knockout on macrophage cholesterol efflux and atherosclerotic plaque development. Circ Res, 124(6):874-880.

[63]Ran D, Shia WJ, Lo MC, et al., 2013. RUNX1a enhances hematopoietic lineage commitment from human embryonic stem cells and inducible pluripotent stem cells. Blood, 121(15):2882-2890.

[64]Robbins PD, Morelli AE, 2014. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol, 14(3):195-208.

[65]Rosa A, Ballarino M, Sorrentino A, et al., 2007. The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. Proc Natl Acad Sci USA, 104(50):19849-19854.

[66]Roush S, Slack FJ, 2008. The let-7 family of microRNAs. Trends Cell Biol, 18(10):505-516.

[67]Schmid MC, Khan SQ, Kaneda MM, et al., 2018. Integrin CD11b activation drives anti-tumor innate immunity. Nat Commun, 9(1):5379.

[68]Schwarzenbach H, Nishida N, Calin GA, et al., 2014. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol, 11(3):145-156.

[69]Selimoglu-Buet D, Rivière J, Ghamlouch H, et al., 2018. A miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset. Nat Commun, 9(1):5455.

[70]Sheedy FJ, Palsson-McDermott E, Hennessy EJ, et al., 2010. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol, 11(2):141-147.

[71]Shidal C, Singh NP, Nagarkatti P, et al., 2019. MicroRNA-92 expression in CD133⁺ melanoma stem cells regulates immunosuppression in the tumor microenvironment via integrin-dependent activation of TGFβ. Cancer Res, 79(14):3622-3635.

[72]Sonda N, Simonato F, Peranzoni E, et al., 2013. miR-142-3p prevents macrophage differentiation during cancer-induced myelopoiesis. Immunity, 38(6):1236-1249.

[73]Squadrito ML, Pucci F, Magri L, et al., 2012. miR-511-3p modulates genetic programs of tumor-associated macrophages. Cell Rep, 1(2):141-154.

[74]Su SC, Zhao QY, He CH, et al., 2015. miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program. Nat Commun, 6:8523.

[75]Suarez-Carmona M, Lesage J, Cataldo D, et al., 2017. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol, 11(7):805-823.

[76]Takano Y, Masuda T, Iinuma H, et al., 2017. Circulating exosomal microRNA-203 is associated with metastasis possibly via inducing tumor-associated macrophages in colorectal cancer. Oncotarget, 8(45):78598-78613.

[77]Talekar M, Trivedi M, Shah P, et al., 2016. Combination wt-p53 and microRNA-125b transfection in a genetically engineered lung cancer model using dual CD44/EGFR-targeting nanoparticles. Mol Ther, 24(4):759-769.

[78]Théry C, Ostrowski M, Segura E, 2009. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol, 9(8):581-593.

[79]Tian YJ, Matsui S, Touma M, et al., 2018. MicroRNA-342 inhibits tumor growth via targeting chemokine CXCL12 involved in macrophages recruitment/activation. Genes Cells, 23(12):1009-1022.

[80]Tili E, Michaille JJ, Cimino A, et al., 2007. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/ TNF-α stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol, 179(8):5082-5089.

[81]Wang P, Hou J, Lin L, et al., 2010. Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J Immunol, 185(10):6226-6233.

[82]Wang P, Xu LJ, Qin JJ, et al., 2018. MicroRNA-155 inversely correlates with esophageal cancer progression through regulating tumor-associated macrophage FGF2 expression. Biochem Biophys Res Commun, 503(2):452-458.

[83]Wang W, Liu Y, Guo J, et al., 2018. miR-100 maintains phenotype of tumor-associated macrophages by targeting mTOR to promote tumor metastasis via Stat5a/IL-1ra pathway in mouse breast cancer. Oncogenesis, 7(12):97.

[84]Wang XF, Luo GT, Zhang KD, et al., 2018. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis. Cancer Res, 78(16):4586-4598.

[85]Wang YF, Wang BY, Xiao S, et al., 2019. miR-125a/b inhibits tumor-associated macrophages mediated in cancer stem cells of hepatocellular carcinoma by targeting CD90. J Cell Biochem, 120(3):3046-3055.

[86]Wang Z, Brandt S, Medeiros A, et al., 2015. MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E₂-mediated M2 generation. PLoS ONE, 10(2):e0115855.

[87]Wei YY, Schober A, 2016. MicroRNA regulation of macrophages in human pathologies. Cell Mol Life Sci, 73(18):3473-3495.

[88]West MA, Heagy W, 2002. Endotoxin tolerance: a review. Crit Care Med, 30(1):S64-S73.

[89]Wilson WR, Hay MP, 2011. Targeting hypoxia in cancer therapy. Nat Rev Cancer, 11(6):393-410.

[90]Xi JJ, Huang Q, Wang L, et al., 2018. miR-21 depletion in macrophages promotes tumoricidal polarization and enhances PD-1 immunotherapy. Oncogene, 37(23):3151-3165.

[91]Yang J, Zhang Z, Chen C, et al., 2014. MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene. Oncogene, 33(23):3014-3023.

[92]Yang M, Chen JQ, Su F, et al., 2011. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer, 10:117.

[93]Yao ZY, Chen WB, Shao SS, et al., 2018. Role of exosome-associated microRNA in diagnostic and therapeutic applications to metabolic disorders. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 19(3):183-198.

[94]Ye JS, Guo RW, Shi YK, et al., 2016. miR-155 regulated inflammation response by the SOCS1-STAT3-PDCD4 axis in atherogenesis. Mediators Inflamm, 2016:8060182.

[95]Yin Y, Yao SR, Hu YL, et al., 2017. The immune-microenvironment confers chemoresistance of colorectal cancer through macrophage-derived IL6. Clin Cancer Res, 23(23):7375-7387.

[96]Ying X, Wu QF, Wu XL, et al., 2016. Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages. Oncotarget, 7(28):43076-43087.

[97]Yona S, Kim KW, Wolf Y, et al., 2013. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity, 38(1):79-91.

[98]Zhang J, Shan WF, Jin TT, et al., 2014. Propofol exerts anti-hepatocellular carcinoma by microvesicle-mediated transfer of miR-142-3p from macrophage to cancer cells. J Transl Med, 12:279.

[99]Zhang W, Liu H, Liu W, et al., 2015. Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-κB pathway. Cell Death Differ, 22(2):287-297.

[100]Zhao HM, Wang XS, Yi P, et al., 2017. KSRP specifies monocytic and granulocytic differentiation through regulating miR-129 biogenesis and RUNX1 expression. Nat Commun, 8(1):1428.

[101]Zhao JL, Huang F, He F, et al., 2016. Forced activation of Notch in macrophages represses tumor growth by upregulating miR-125a and disabling tumor-associated macrophages. Cancer Res, 76(6):1403-1415.

[102]Zhao Y, Zou WL, Du JF, et al., 2018. The origins and homeostasis of monocytes and tissue-resident macrophages in physiological situation. J Cell Physiol, 233(10):6425-6439.

[103]Zheng PM, Chen L, Yuan XL, et al., 2017. Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells. J Exp Clin Cancer Res, 36(1):53.

[104]Zhou HB, Huang XF, Cui HJ, et al., 2010. miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells. Blood, 116(26):5885-5894.

[105]Zhou JR, Li XD, Wu XL, et al., 2018. Exosomes released from tumor-associated macrophages transfer miRNAs that induce a Treg/Th17 cell imbalance in epithelial ovarian cancer. Cancer Immunol Res, 6(12):1578-1592.

[106]Zhou SL, Hu ZQ, Zhou ZJ, et al., 2016. miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. Hepatology, 63(5):1560-1575.

[107]Zhu XL, Shen HL, Yin XM, et al., 2019. Macrophages derived exosomes deliver miR-223 to epithelial ovarian cancer cells to elicit a chemoresistant phenotype. J Exp Clin Cancer Res, 38(1):81.