Protein & Cell

, Volume 3, Issue 1, pp 28–37 | Cite as

Horizontal transfer of microRNAs: molecular mechanisms and clinical applications

  • Xi Chen
  • Hongwei Liang
  • Junfeng ZhangEmail author
  • Ke ZenEmail author
  • Chen-Yu ZhangEmail author


A new class of RNA regulatory genes known as microRNAs (miRNAs) has been found to introduce a whole new layer of gene regulation in eukaryotes. The intensive studies of the past several years have demonstrated that miRNAs are not only found intracellularly, but are also detectable outside cells, including in various body fluids (e.g. serum, plasma, saliva, urine and milk). This phenomenon raises questions about the biological function of such extracellular miRNAs. Substantial amounts of extracellular miRNAs are enclosed in small membranous vesicles (e.g. exosomes, shedding vesicles and apoptotic bodies) or packaged with RNA-binding proteins (e.g. high-density lipoprotein, Argonaute 2 and nucleophosmin 1). These miRNAs may function as secreted signaling molecules to influence the recipient cell phenotypes. Furthermore, secreted extracellular miRNAs may reflect molecular changes in the cells from which they are derived and can therefore potentially serve as diagnostic indicators of disease. Several studies also point to the potential application of siRNA/miRNA delivery as a new therapeutic strategy for treating diseases. In this review, we summarize what is known about the mechanism of miRNA secretion. In addition, we describe the pathophysiological roles of secreted miRNAs and their clinical potential as diagnostic biomarkers and therapeutic drugs. We believe that miRNA transfer between cells will have a significant impact on biological research in the coming years.


microRNA extracellular microRNA microRNA secretion horizontal transfer microvesicle exosome apoptotic body high-density lipoprotein Argonaute 2 nucleophosmin 1 diagnosis therapy 


  1. Ahmed, K.A., and Xiang, J. (2011). Mechanisms of cellular communication through intercellular protein transfer. J Cell Mol Med 15, 1458–1473.CrossRefGoogle Scholar
  2. Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., and Wood, M.J. (2011). Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29, 341–345.CrossRefGoogle Scholar
  3. Ambros, V. (2004). The functions of animal microRNAs. Nature 431, 350–355.CrossRefGoogle Scholar
  4. Arroyo, J.D., Chevillet, J.R., Kroh, E.M., Ruf, I.K., Pritchard, C.C., Gibson, D.F., Mitchell, P.S., Bennett, C.F., Pogosova-Agadjanyan, E.L., Stirewalt, D.L., et al. (2011). Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 108, 5003–5008.CrossRefGoogle Scholar
  5. Bartel, D.P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297.CrossRefGoogle Scholar
  6. Belting, M., and Wittrup, A. (2008). Nanotubes, exosomes, and nucleic acid-binding peptides provide novel mechanisms of intercellular communication in eukaryotic cells: implications in health and disease. J Cell Biol 183, 1187–1191.CrossRefGoogle Scholar
  7. Bergsmedh, A., Szeles, A., Henriksson, M., Bratt, A., Folkman, M.J., Spetz, A.L., and Holmgren, L. (2001). Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc Natl Acad Sci U S A 98, 6407–6411.CrossRefGoogle Scholar
  8. Calin, G.A., and Croce, C.M. (2006). MicroRNA signatures in human cancers. Nat Rev Cancer 6, 857–866.CrossRefGoogle Scholar
  9. Chen, X., Ba, Y., Ma, L., Cai, X., Yin, Y., Wang, K., Guo, J., Zhang, Y., Chen, J., Guo, X., et al. (2008). Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18, 997–1006.CrossRefGoogle Scholar
  10. Chen, X., Gao, C., Li, H., Huang, L., Sun, Q., Dong, Y., Tian, C., Gao, S., Dong, H., Guan, D., et al. (2010). Identification and characterization of microRNAs in raw milk during different periods of lactation, commercial fluid, and powdered milk products. Cell Res 20, 1128–1137.CrossRefGoogle Scholar
  11. Cocucci, E., Racchetti, G., and Meldolesi, J. (2009). Shedding microvesicles: artefacts no more. Trends Cell Biol 19, 43–51.CrossRefGoogle Scholar
  12. Collino, F., Deregibus, M.C., Bruno, S., Sterpone, L., Aghemo, G., Viltono, L., Tetta, C., and Camussi, G. (2010). Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One 5, e11803.CrossRefGoogle Scholar
  13. Davis, D.M. (2007). Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response. Nat Rev Immunol 7, 238–243.CrossRefGoogle Scholar
  14. Deregibus, M.C., Cantaluppi, V., Calogero, R., Lo Iacono, M., Tetta, C., Biancone, L., Bruno, S., Bussolati, B., and Camussi, G. (2007). Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 110, 2440–2448.CrossRefGoogle Scholar
  15. Dunning Hotopp, J.C. (2011). Horizontal gene transfer between bacteria and animals. Trends Genet 27, 157–163.CrossRefGoogle Scholar
  16. Esquela-Kerscher, A., and Slack, F.J. (2006). Oncomirs — microRNAs with a role in cancer. Nat Rev Cancer 6, 259–269.CrossRefGoogle Scholar
  17. Gourzones, C., Gelin, A., Bombik, I., Klibi, J., Vérillaud, B., Guigay, J., Lang, P., Témam, S., Schneider, V., Amiel, C., et al. (2010). Extracellular release and blood diffusion of BART viral micro-RNAs produced by EBV-infected nasopharyngeal carcinoma cells. Virol J 7, 271.CrossRefGoogle Scholar
  18. Hanke, M., Hoefig, K., Merz, H., Feller, A.C., Kausch, I., Jocham, D., Warnecke, J.M., and Sczakiel, G. (2010). A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer. Urol Oncol 28, 655–661.CrossRefGoogle Scholar
  19. Hata, T., Murakami, K., Nakatani, H., Yamamoto, Y., Matsuda, T., and Aoki, N. (2010). Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs. Biochem Biophys Res Commun 396, 528–533.CrossRefGoogle Scholar
  20. He, L., and Hannon, G.J. (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5, 522–531.CrossRefGoogle Scholar
  21. Holmgren, L. (2010). Horizontal gene transfer: you are what you eat. Biochem Biophys Res Commun 396, 147–151.CrossRefGoogle Scholar
  22. Holmgren, L., Szeles, A., Rajnavölgyi, E., Folkman, J., Klein, G., Ernberg, I., and Falk, K.I. (1999). Horizontal transfer of DNA by the uptake of apoptotic bodies. Blood 93, 3956–3963.Google Scholar
  23. Hunter, M.P., Ismail, N., Zhang, X.L., Aguda, B.D., Lee, E.J., Yu, L.B., Xiao, T., Schafer, J., Lee, M.L.T., Schmittgen, T.D., et al. (2008). Detection of microRNA expression in human peripheral blood microvesicles. PLoS One 3, e3694.CrossRefGoogle Scholar
  24. Hutvágner, G., McLachlan, J., Pasquinelli, A.E., Bálint, E., Tuschl, T., and Zamore, P.D. (2001). A cellular function for the RNAinterference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293, 834–838.CrossRefGoogle Scholar
  25. Ji, X., Takahashi, R., Hiura, Y., Hirokawa, G., Fukushima, Y., and Iwai, N. (2009). Plasma miR-208 as a biomarker of myocardial injury. Clin Chem 55, 1944–1949.CrossRefGoogle Scholar
  26. Keeling, P.J., and Palmer, J.D. (2008). Horizontal gene transfer in eukaryotic evolution. Nat Rev Genet 9, 605–618.CrossRefGoogle Scholar
  27. Khvorova, A., Reynolds, A., and Jayasena, S.D. (2003). Functional siRNAs and miRNAs exhibit strand bias. Cell 115, 209–216.CrossRefGoogle Scholar
  28. Kosaka, N., Iguchi, H., Yoshioka, Y., Takeshita, F., Matsuki, Y., and Ochiya, T. (2010a). Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285, 17442–17452.CrossRefGoogle Scholar
  29. Kosaka, N., Izumi, H., Sekine, K., and Ochiya, T. (2010b). microRNA as a new immune-regulatory agent in breast milk. Silence 1, 7CrossRefGoogle Scholar
  30. Laterza, O.F., Lim, L., Garrett-Engele, P.W., Vlasakova, K., Muniappa, N., Tanaka, W.K., Johnson, J.M., Sina, J.F., Fare, T.L., Sistare, F. D., et al. (2009). Plasma MicroRNAs as sensitive and specific biomarkers of tissue injury. Clin Chem 55, 1977–1983.CrossRefGoogle Scholar
  31. Lawrie, C.H., Gal, S., Dunlop, H.M., Pushkaran, B., Liggins, A.P., Pulford, K., Banham, A.H., Pezzella, F., Boultwood, J., Wainscoat, J.S., et al. (2008). Detection of elevated levels of tumourassociated microRNAs in serum of patients with diffuse large Bcell lymphoma. Br J Haematol 141, 672–675.CrossRefGoogle Scholar
  32. Lee, Y., Ahn, C., Han, J., Choi, H., Kim, J., Yim, J., Lee, J., Provost, P., Rådmark, O., Kim, S., et al. (2003). The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419.CrossRefGoogle Scholar
  33. Lee, Y., Kim, M., Han, J., Yeom, K.H., Lee, S., Baek, S.H., and Kim, V. N. (2004). MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23, 4051–4060.CrossRefGoogle Scholar
  34. Lund, E., Güttinger, S., Calado, A., Dahlberg, J.E., and Kutay, U. (2004). Nuclear export of microRNA precursors. Science 303, 95–98.CrossRefGoogle Scholar
  35. Luo, S.S., Ishibashi, O., Ishikawa, G., Ishikawa, T., Katayama, A., Mishima, T., Takizawa, T., Shigihara, T., Goto, T., Izumi, A., et al. (2009). Human villous trophoblasts express and secrete placentaspecific microRNAs into maternal circulation via exosomes. Biol Reprod 81, 717–729.CrossRefGoogle Scholar
  36. Meckes, D.G. Jr, Shair, K.H.Y., Marquitz, A.R., Kung, C.P., Edwards, R.H., and Raab-Traub, N. (2010). Human tumor virus utilizes exosomes for intercellular communication. Proc Natl Acad Sci U S A 107, 20370–20375.CrossRefGoogle Scholar
  37. Mitchell, P.S., Parkin, R.K., Kroh, E.M., Fritz, B.R., Wyman, S.K., Pogosova-Agadjanyan, E.L., Peterson, A., Noteboom, J., O’Briant, K.C., Allen, A., et al. (2008). Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105, 10513–10518.CrossRefGoogle Scholar
  38. Mittelbrunn, M., Gutiérrez-Vázquez, C., Villarroya-Beltri, C., González, S., Sánchez-Cabo, F., González, M.A., Bernad, A., and Sánchez-Madrid, F. (2011). Unidirectional transfer of microRNAloaded exosomes from T cells to antigen-presenting cells. Nat Commun 2, 282.CrossRefGoogle Scholar
  39. Müller, G., Schneider, M., Biemer-Daub, G., and Wied, S. (2011). Microvesicles released from rat adipocytes and harboring glycosylphosphatidylinositol-anchored proteins transfer RNA stimulating lipid synthesis. Cell Signal 23, 1207–1223.CrossRefGoogle Scholar
  40. Muralidharan-Chari, V., Clancy, J.W., Sedgwick, A., and D’souza-Schorey, C. (2010). Microvesicles: mediators of extracellular communication during cancer progression. J Cell Sci 123, 1603–1611.CrossRefGoogle Scholar
  41. Ogawa, R., Tanaka, C., Sato, M., Nagasaki, H., Sugimura, K., Okumura, K., Nakagawa, Y., and Aoki, N. (2010). Adipocytederived microvesicles contain RNA that is transported into macrophages and might be secreted into blood circulation. Biochem Biophys Res Commun 398, 723–729.CrossRefGoogle Scholar
  42. Ohshima, K., Inoue, K., Fujiwara, A., Hatakeyama, K., Kanto, K., Watanabe, Y., Muramatsu, K., Fukuda, Y., Ogura, S., Yamaguchi, K., et al. (2010). Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One 5, e13247.CrossRefGoogle Scholar
  43. Park, N.J., Zhou, H., Elashoff, D., Henson, B.S., Kastratovic, D.A., Abemayor, E., and Wong, D.T. (2009). Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res 15, 5473–5477.CrossRefGoogle Scholar
  44. Pegtel, D.M., Cosmopoulos, K., Thorley-Lawson, D.A., van Eijndhoven, M.A.J., Hopmans, E.S., Lindenberg, J.L., de Gruijl, T.D., Würdinger, T., and Middeldorp, J.M. (2010). Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci U S A 107, 6328–6333.CrossRefGoogle Scholar
  45. Pfeffer, S., Zavolan, M., Grässer, F.A., Chien, M.C., Russo, J.J., Ju, J. Y., John, B., Enright, A.J., Marks, D., Sander, C., et al. (2004). Identification of virus-encoded microRNAs. Science 304, 734–736.CrossRefGoogle Scholar
  46. Rabinowits, G., Gerçel-Taylor, C., Day, J.M., Taylor, D.D., and Kloecker, G.H. (2009). Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer 10, 42–46.CrossRefGoogle Scholar
  47. Ratajczak, J., Miekus, K., Kucia, M., Zhang, J., Reca, R., Dvorak, P., and Ratajczak, M.Z. (2006). Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20, 847–856.CrossRefGoogle Scholar
  48. Rechavi, O., Goldstein, I., and Kloog, Y. (2009). Intercellular exchange of proteins: the immune cell habit of sharing. FEBS Lett 583, 1792–1799.CrossRefGoogle Scholar
  49. Ryther, R.C., Flynt, A.S., Phillips, J.A. 3rd, and Patton, J.G. (2005). siRNA therapeutics: big potential from small RNAs. Gene Ther 12, 5–11.CrossRefGoogle Scholar
  50. Schwarz, D.S., Hutvágner, G., Du, T., Xu, Z., Aronin, N., and Zamore, P.D. (2003). Asymmetry in the assembly of the RNAi enzyme complex. Cell 115, 199–208.CrossRefGoogle Scholar
  51. Simons, M., and Raposo, G. (2009). Exosomes-vesicular carriers for intercellular communication. Curr Opin Cell Biol 21, 575–581.CrossRefGoogle Scholar
  52. Skog, J., Würdinger, T., van Rijn, S., Meijer, D.H., Gainche, L., Sena-Esteves, M., Curry, W.T. Jr, Carter, B.S., Krichevsky, A.M., and Breakefield, X.O. (2008). Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10, 1470–1476.CrossRefGoogle Scholar
  53. Taylor, D.D., and Gercel-Taylor, C. (2008). MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110, 13–21.CrossRefGoogle Scholar
  54. Théry, C., Zitvogel, L., and Amigorena, S. (2002). Exosomes: composition, biogenesis and function. Nat Rev Immunol 2, 569–579.Google Scholar
  55. Turchinovich, A., Weiz, L., Langheinz, A., and Burwinkel, B. (2011). Characterization of extracellular circulating microRNA. Nucleic Acids Res 39, 7223–7233.CrossRefGoogle Scholar
  56. Valadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J.J., and Lötvall, J.O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9, 654–659.CrossRefGoogle Scholar
  57. van Rooij, E., and Olson, E.N. (2007). MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets. J Clin Invest 117, 2369–2376.CrossRefGoogle Scholar
  58. Vickers, K.C., Palmisano, B.T., Shoucri, B.M., Shamburek, R.D., and Remaley, A.T. (2011). MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13, 423–433.CrossRefGoogle Scholar
  59. Wang, K., Zhang, S., Marzolf, B., Troisch, P., Brightman, A., Hu, Z., Hood, L.E., and Galas, D.J. (2009). Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci U S A 106, 4402–4407.CrossRefGoogle Scholar
  60. Wang, K., Zhang, S.L., Weber, J., Baxter, D., and Galas, D.J. (2010). Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res 38, 7248–7259.CrossRefGoogle Scholar
  61. Weiler, J., Hunziker, J., and Hall, J. (2006). Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease? Gene Ther 13, 496–502.CrossRefGoogle Scholar
  62. Yuan, A., Farber, E.L., Rapoport, A.L., Tejada, D., Deniskin, R., Akhmedov, N.B., and Farber, D.B. (2009). Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One 4, e4722.CrossRefGoogle Scholar
  63. Zernecke, A., Bidzhekov, K., Noels, H., Shagdarsuren, E., Gan, L., Denecke, B., Hristov, M., Köppel, T., Jahantigh, M.N., Lutgens, E. et al. (2009). Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal 2, ra81.CrossRefGoogle Scholar
  64. Zhang, Y.J., Liu, D.Q., Chen, X., Li, J., Li, L.M., Bian, Z., Sun, F., Lu, J. W., Yin, Y.A., Cai, X., et al. (2010). Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 39, 133–144.CrossRefGoogle Scholar

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© Higher Education Press and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life SciencesNanjing UniversityNanjingChina

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