Abstract
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.
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Ahmed, K.A., and Xiang, J. (2011). Mechanisms of cellular communication through intercellular protein transfer. J Cell Mol Med 15, 1458–1473.
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.
Ambros, V. (2004). The functions of animal microRNAs. Nature 431, 350–355.
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.
Bartel, D.P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297.
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.
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.
Calin, G.A., and Croce, C.M. (2006). MicroRNA signatures in human cancers. Nat Rev Cancer 6, 857–866.
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.
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.
Cocucci, E., Racchetti, G., and Meldolesi, J. (2009). Shedding microvesicles: artefacts no more. Trends Cell Biol 19, 43–51.
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.
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.
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.
Dunning Hotopp, J.C. (2011). Horizontal gene transfer between bacteria and animals. Trends Genet 27, 157–163.
Esquela-Kerscher, A., and Slack, F.J. (2006). Oncomirs — microRNAs with a role in cancer. Nat Rev Cancer 6, 259–269.
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.
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.
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.
He, L., and Hannon, G.J. (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5, 522–531.
Holmgren, L. (2010). Horizontal gene transfer: you are what you eat. Biochem Biophys Res Commun 396, 147–151.
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.
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.
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.
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.
Keeling, P.J., and Palmer, J.D. (2008). Horizontal gene transfer in eukaryotic evolution. Nat Rev Genet 9, 605–618.
Khvorova, A., Reynolds, A., and Jayasena, S.D. (2003). Functional siRNAs and miRNAs exhibit strand bias. Cell 115, 209–216.
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.
Kosaka, N., Izumi, H., Sekine, K., and Ochiya, T. (2010b). microRNA as a new immune-regulatory agent in breast milk. Silence 1, 7
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.
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.
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.
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.
Lund, E., Güttinger, S., Calado, A., Dahlberg, J.E., and Kutay, U. (2004). Nuclear export of microRNA precursors. Science 303, 95–98.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Rechavi, O., Goldstein, I., and Kloog, Y. (2009). Intercellular exchange of proteins: the immune cell habit of sharing. FEBS Lett 583, 1792–1799.
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.
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.
Simons, M., and Raposo, G. (2009). Exosomes-vesicular carriers for intercellular communication. Curr Opin Cell Biol 21, 575–581.
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.
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.
Théry, C., Zitvogel, L., and Amigorena, S. (2002). Exosomes: composition, biogenesis and function. Nat Rev Immunol 2, 569–579.
Turchinovich, A., Weiz, L., Langheinz, A., and Burwinkel, B. (2011). Characterization of extracellular circulating microRNA. Nucleic Acids Res 39, 7223–7233.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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Chen, X., Liang, H., Zhang, J. et al. Horizontal transfer of microRNAs: molecular mechanisms and clinical applications. Protein Cell 3, 28–37 (2012). https://doi.org/10.1007/s13238-012-2003-z
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DOI: https://doi.org/10.1007/s13238-012-2003-z