Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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MicroRNA 449c Mediates the Generation of Monocytic Myeloid-Derived Suppressor Cells by Targeting STAT6

  • Han, Xiaoqing (The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University) ;
  • Luan, Tao (The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University) ;
  • Sun, Yingying (The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University) ;
  • Yan, Wenyi (The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University) ;
  • Wang, Dake (The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University) ;
  • Zeng, Xianlu (The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University)
  • Received : 2019.12.06
  • Accepted : 2020.08.10
  • Published : 2020.09.30
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Abstract

Myeloid-derived suppressor cells (MDSCs) promote tumour progression by contributing to angiogenesis, immunosuppression, and immunotherapy resistance. Although recent studies have shown that microRNAs (miRNAs) can promote the expansion of MDSCs in the tumour environment, the mechanisms involved in this process are largely unknown. Here, we report that microRNA 449c (miR-449c) expression was upregulated in myeloid progenitor cells upon activation of C-X-C motif chemokine receptor 2 (CXCR2) under tumour conditions. MiR-449c upregulation increased the generation of monocytic MDSCs (mo-MDSCs). The increased expression of miR-449c could target STAT6 mRNA in myeloid progenitor cells to shift the differentiation balance of myeloid progenitor cells and lead to an enhancement of the mo-MDSCs population in the tumour environment. Thus, our results demonstrate that the miR-449c/STAT6 axis is involved in the expansion of mo-MDSCs from myeloid progenitor cells upon activation of CXCR2, and thus, inhibition of miR-449c/STAT6 signalling may help to attenuate tumour progression.

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References

  1. Bartel, D.P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281-297. https://doi.org/10.1016/S0092-8674(04)00045-5
  2. Chatterjee, S., Das, S., Chakraborty, P., Manna, A., Chatterjee, M., and Choudhuri, S.K. (2013). Myeloid derived suppressor cells (MDSCs) can induce the generation of Th17 response from naive CD4+ T cells. Immunobiology 218, 718-724. https://doi.org/10.1016/j.imbio.2012.08.271
  3. Chen, S., Zhang, Y., Kuzel, T.M., and Zhang, B. (2015). Regulating tumor myeloid-derived suppressor cells by microRNAs. Cancer Cell Microenviron. 2, e637.
  4. Chen, X., Wang, A., and Yue, X. (2018). miR-449c inhibits migration and invasion of gastric cancer cells by targeting PFKFB3. Oncol. Lett. 16, 417-424.
  5. Chomarat, P., Banchereau, J., Davoust, J., and Palucka, A.K. (2000). IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat. Immunol. 1, 510-514. https://doi.org/10.1038/82763
  6. Condamine, T., Mastio, J., and Gabrilovich, D.I. (2015). Transcriptional regulation of myeloid-derived suppressor cells. J. Leukoc. Biol. 98, 913-922. https://doi.org/10.1189/jlb.4RI0515-204R
  7. De Tullio, G., De Fazio, V., Sgherza, N., Minoia, C., Serrati, S., Merchionne, F., Loseto, G., Iacobazzi, A., Rana, A., Petrillo, P., et al. (2014). Challenges and opportunities of microRNAs in lymphomas. Molecules 19, 14723-14781. https://doi.org/10.3390/molecules190914723
  8. El Gazzar, M. (2014). microRNAs as potential regulators of myeloidderived suppressor cell expansion. Innate Immun. 20, 227-38. https://doi.org/10.1177/1753425913489850
  9. Friedman, A.D. (2015). C/EBPalpha in normal and malignant myelopoiesis. Int. J. Hematol. 101, 330-341. https://doi.org/10.1007/s12185-015-1764-6
  10. Gabrilovich, D.I., Ostrand-Rosenberg, S., and Bronte, V. (2012). Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253-268. https://doi.org/10.1038/nri3175
  11. Goddard, S., Youster, J., Morgan, E., and Adams, D.H. (2004). Interleukin-10 secretion differentiates dendritic cells from human liver and skin. Am. J. Pathol. 164, 511-519. https://doi.org/10.1016/S0002-9440(10)63141-0
  12. Halliday, G.M. and Le, S. (2001). Transforming growth factor-beta produced by progressor tumors inhibits, while IL-10 produced by regressor tumors enhances, Langerhans cell migration from skin. Int. Immunol. 13, 1147-1154. https://doi.org/10.1093/intimm/13.9.1147
  13. Han, X., Shi, H., Sun, Y., Shang, C., Luan, T., Wang, D., Ba, X., and Zeng, X. (2019). CXCR2 expression on granulocyte and macrophage progenitors under tumor conditions contributes to mo-MDSC generation via SAP18/ERK/STAT3. Cell Death Dis. 10, 598. https://doi.org/10.1038/s41419-019-1837-1
  14. Hoechst, B., Voigtlaender, T., Ormandy, L., Gamrekelashvili, J., Zhao, F., Wedemeyer, H., Lehner, F., Manns, M.P., Greten, T.F., and Korangy, F. (2009). Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50, 799-807. https://doi.org/10.1002/hep.23054
  15. Hong, S.H., Kim, K.S., and Oh, I.H. (2015). Concise review: exploring miRNAs--toward a better understanding of hematopoiesis. Stem Cells 33, 1-7. https://doi.org/10.1002/stem.1810
  16. Jayakumar, A. and Bothwell, A. (2017). Stat6 promotes intestinal tumorigenesis in a mouse model of adenomatous polyposis by expansion of MDSCs and inhibition of cytotoxic CD8 response. Neoplasia 19, 595-605. https://doi.org/10.1016/j.neo.2017.04.006
  17. Jing, H., Vassiliou, E., and Ganea, D. (2003). Prostaglandin E2 inhibits production of the inflammatory chemokines CCL3 and CCL4 in dendritic cells. J. Leukoc. Biol. 74, 868-879. https://doi.org/10.1189/jlb.0303116
  18. Kim, M., Civin, C.I., and Kingsbury, T.J. (2019). MicroRNAs as regulators and effectors of hematopoietic transcription factors. Wiley Interdiscip. Rev. RNA 10, e1537.
  19. Ko, J.S., Zea, A.H., Rini, B.I., Ireland, J.L., Elson, P., Cohen, P., Golshayan, A., Rayman, P.A., Wood, L., Garciaet, L., et al. (2009). Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin. Cancer Res. 15, 2148-2157. https://doi.org/10.1158/1078-0432.CCR-08-1332
  20. Leon-Cabrera, S.A., Molina-Guzman, E., Delgado-Ramirez, Y.G., VázquezSandoval, A., Ledesma-Soto, Y., Pérez-Plasencia, C.G., Chirino, Y.I., DelgadoBuenrostro, N.L., Rodríguez-Sosa, M., Vaca-Paniagua, F., et al. (2017). Lack of STAT6 attenuates inflammation and drives protection against early steps of colitis-associated colon cancer. Cancer Immunol. Res. 5, 385-396. https://doi.org/10.1158/2326-6066.CIR-16-0168
  21. Majumder, M., Landman, E., Liu, L., Hess, D., and Lala, P.K. (2015). COX2 elevates oncogenic miR-526b in breast cancer by EP4 activation. Mol. Cancer Res. 13, 1022-1033. https://doi.org/10.1158/1541-7786.MCR-14-0543
  22. Marigo, I., Bosio, E., Solito, S., Mesa, C., Fernandez, A., Dolcetti, L., Ugel, S., Sonda, N., Bicciato, S., Falisi, E., et al. (2010). Tumor- induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 32, 790-802. https://doi.org/10.1016/j.immuni.2010.05.010
  23. Miao, L.J., Huang, S.F., Sun, Z.T., Gao, Z.Y., Zhang, R.X., Liu, Y., and Wang, J. (2013). MiR-449c targets c-Myc and inhibits NSCLC cell progression. FEBS Lett. 587, 1359-1365. https://doi.org/10.1016/j.febslet.2013.03.006
  24. Movahedi, K., Guilliams, M., Van den Bossche, J., Van den Bergh, R., Gysemans, C., Beschin, A., Baetselier, P.D., and Ginderachter J.A. (2008). Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111, 4233-4244. https://doi.org/10.1182/blood-2007-07-099226
  25. Munera, V., Popovic, P.J., Bryk, J., Pribis, J., Caba, D., Matta, B.M., Zenati, M., and Ochoa, J.B. (2010). Stat 6-dependent induction of myeloid derived suppressor cells after physical injury regulates nitric oxide response to endotoxin. Ann. Surg. 251, 120-126. https://doi.org/10.1097/SLA.0b013e3181bfda1c
  26. Nagaraj, S. and Gabrilovich, D.I. (2010). Myeloid-derived suppressor cells in human cancer. Cancer J. 16, 348-353. https://doi.org/10.1097/PPO.0b013e3181eb3358
  27. Ostrand-Rosenberg, S. and Sinha, P. (2009). Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 182, 4499-4506. https://doi.org/10.4049/jimmunol.0802740
  28. Poh, T.W., Bradley, J.M., Mukherjee, P., and Gendler, S.J. (2009). Lack of Muc1-regulated beta-catenin stability results in aberrant expansion of CD11b+Gr1+ myeloid-derived suppressor cells from the bone marrow. Cancer Res. 69, 3554-3562. https://doi.org/10.1158/0008-5472.CAN-08-3806
  29. Raber, P.L., Thevenot, P., Sierra, R., Wyczechowska, D., Halle, D., Cheng, P.Y., Villagra, A., Antonia, S., McCaffrey, J.C., Fishman, M., et al. (2014). Subpopulations of myeloid-derived suppressor cells impair T cell responses through independent nitric oxide-related pathways. Int. J. Cancer 134, 2853-2864. https://doi.org/10.1002/ijc.28622
  30. Ren, X., Bai, X., Zhang, X., Li, Z., Tang, L., Zhao, Y.X., Li, Z.Y., Ren, Y.F., Wei, S.C., Wang, Q.S., et al. (2015). Quantitative nuclear proteomics identifies that miR-137-mediated EZH2 reduction regulates resveratrol-induced apoptosis of neuroblastoma cells. Mol. Cell. Proteomics 14, 316-328. https://doi.org/10.1074/mcp.M114.041905
  31. Roth, F., De La Fuente, A.C., Vella, J.L., Zoso, A., Inverardi, L., and Serafini, P. (2012). Aptamer-mediated blockade of IL4Ralpha triggers apoptosis of MDSCs and limits tumor progression. Cancer Res. 72, 1373-1383. https://doi.org/10.1158/0008-5472.CAN-11-2772
  32. Saki, N., Abroun, S., Soleimani, M., Hajizamani, S., Shahjahani, M., Kast, R.E., and Mortazavi, Y. (2015). Involvement of microRNA in T- cell differentiation and malignancy. Int. J. Hematol. Oncol. Stem Cell Res. 9, 33-49.
  33. Sandbothe, M., Buurman, R., Reich, N., Greiwe, L., Vajen B., Gürlevik, E., Schäffer, V., Eilers, M., Kühnel, F., Vaquero, A., et al. (2017). The microRNA-449 family inhibits TGF-beta-mediated liver cancer cell migration by targeting SOX4. J. Hepatol. 66, 1012-1021. https://doi.org/10.1016/j.jhep.2017.01.004
  34. Shi, H., Han, X., Sun, Y., Shang, C., Wei, M., Ba, X., and Zeng, X. (2018). Chemokine (C-X-C motif) ligand 1 and CXCL2 produced by tumor promote the generation of monocytic myeloid-derived suppressor cells. Cancer Sci. 109, 3826-3839. https://doi.org/10.1111/cas.13809
  35. Wang, J., De Veirman, K., De Beule, N., Maes, K., De Bruyne, E., Vanderkerken, K., and Menu, E. (2015). The bone marrow microenvironment enhances multiple myeloma progression by exosomemediated activation of myeloid-derived suppressor cells. Oncotarget 6,43992-44004. https://doi.org/10.18632/oncotarget.6083
  36. Wang, J., Su, X., Yang, L., Qiao, F., Fang, Y., Fang, F., Yu, L., Yang, Q., Wang, Y.Y., Yin, Y.F., et al. (2016). The influence of myeloid- derived suppressor cells on angiogenesis and tumor growth after cancer surgery. Int. J. Cancer 138, 2688-2699. https://doi.org/10.1002/ijc.29998
  37. Wu, J., Bao, J., Kim, M., Yuan, S., Tang, C., Zheng, H., Mastick, G.S., Xu, C., and Yan, W. (2014). Two miRNA clusters, miR-34b/c and miR-449, are essential for normal brain development, motile ciliogenesis, and spermatogenesis. Proc. Natl. Acad. Sci. U. S. A. 111, E2851-E2857. https://doi.org/10.1073/pnas.1407777111
  38. Ye, X.Z., Yu, S.C., and Bian, X.W. (2010). Contribution of myeloid- derived suppressor cells to tumor-induced immune suppression, angiogenesis, invasion and metastasis. J. Genet. Genomics 37, 423- 430. https://doi.org/10.1016/S1673-8527(09)60061-8
  39. Youn, J.I., Kumar, V., Collazo, M., Nefedova, Y., Condamine, T., Cheng, P., Villagra, A., Antonia, S., McCaffrey, J.C., Fishmanet, M., et al. (2013). Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat. Immunol. 14, 211-220. https://doi.org/10.1038/ni.2526
  40. Zang, W., Wang, Y., Wang, T., Du, Y., Chen, X., Li, M., and Zhao, G.Q. (2015). miR-663 attenuates tumor growth and invasiveness by targeting eEF1A2 in pancreatic cancer. Mol. Cancer 14, 37. https://doi.org/10.1186/s12943-015-0315-3

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