1932

Abstract

Various biotypes of endogenous small RNAs (sRNAs) have been detected in human circulation, including microRNAs, transfer RNAs, ribosomal RNA, and yRNA fragments. These extracellular sRNAs (ex-sRNAs) are packaged and secreted by many different cell types. Ex-sRNAs exhibit differences in abundance in several disease states and have, therefore, been proposed for use as effective biomarkers. Furthermore, exosome-borne ex-sRNAs have been reported to elicit physiological responses in acceptor cells. Exogenous ex-sRNAs derived from diet (most prominently from plants) and microorganisms have also been reported in human blood. Essential issues that remain to be conclusively addressed concern the () presence and sources of exogenous ex-sRNAs in human bodily fluids, () detection and measurement of ex-sRNAs in human circulation, () selectivity of ex-sRNA export and import, () sensitivity and specificity of ex-sRNA delivery to cellular targets, and () cell-, tissue-, organ-, and organism-wide impacts of ex-sRNA-mediated cell-to-cell communication. We survey the present state of knowledge of most of these issues in this review.

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2016-07-17
2024-04-23
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Literature Cited

  1. Abdullah Z, Schlee M, Roth S, Mraheil MA, Barchet W. 1.  et al. 2012. RIG-I detects infection with live Listeria by sensing secreted bacterial nucleic acids. EMBO J. 31:214153–64 [Google Scholar]
  2. Aird D, Ross MG, Chen W-S, Danielsson M, Fennell T. 2.  et al. 2011. Analyzing and minimizing PCR amplification bias in Illumina sequencing libraries. Genome Biol. 12:2R18 [Google Scholar]
  3. Akat KM, Moore-McGriff D, Morozov P, Brown M, Gogakos T. 3.  et al. 2014. Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers. PNAS 111:3011151–56 [Google Scholar]
  4. Akay A, Sarkies P, Miska EA. 4.  2015. E. coli OxyS non-coding RNA does not trigger RNAi in C. elegans. Sci. Rep. 5:9597 [Google Scholar]
  5. Akers JC, Gonda D, Kim R, Carter BS, Chen CC. 5.  2013. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J. Neuro-Oncology 113:11–11 [Google Scholar]
  6. Akers JC, Ramakrishnan V, Kim R, Skog J, Nakano I. 6.  et al. 2013. Mir-21 in the extracellular vesicles (EVs) of cerebrospinal fluid (CSF): a platform for glioblastoma biomarker development. PLOS ONE 8:10e78115 [Google Scholar]
  7. Allegra A, Alonci A, Campo S, Penna G, Petrungaro A, Gerace D MC. 7.  2012. Circulating microRNAs: new biomarkers in diagnosis, prognosis and treatment of cancer (review). Int. J. Oncol. 41:61897–912 [Google Scholar]
  8. Almanza G, Anufreichik V, Rodvold JJ, Chiu KT, DeLaney A. 8.  et al. 2013. Synthesis and delivery of short, noncoding RNA by B lymphocytes. PNAS 110:5020182–87 [Google Scholar]
  9. Anders S, Huber W. 9.  2010. Differential expression analysis for sequence count data. Genome Biol. 11:10R106 [Google Scholar]
  10. Anderson MT, Seifert HS. 10.  2011. Opportunity and means: horizontal gene transfer from the human host to a bacterial pathogen. mBio 2:1e00005–00011 [Google Scholar]
  11. Anderson P, Ivanov P. 11.  2014. tRNA fragments in human health and disease. FEBS Lett. 588:234297–304 [Google Scholar]
  12. Appaiah HN, Goswami CP, Mina L, Badve S, Sledge GW. 12.  et al. 2011. Persistent upregulation of U6:SNORD44 small RNA ratio in the serum of breast cancer patients. Breast Cancer Res. 13:5R86 [Google Scholar]
  13. Archambaud C, Sismeiro O, Toedling J, Soubigou G, Bécavin C. 13.  et al. 2013. The intestinal microbiota interferes with the microRNA response upon oral Listeria infection. mBio 4:6e00707–13 [Google Scholar]
  14. Arkov AL, Mankin A, Murgola EJ. 14.  1998. An rRNA fragment and its antisense can alter decoding of genetic information. J. Bacteriol. 180:102744–48 [Google Scholar]
  15. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC. 15.  et al. 2011. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. PNAS 108:125003–8 [Google Scholar]
  16. Bahn JH, Zhang Q, Li F, Chan T-M, Lin X. 16.  et al. 2015. The landscape of microRNA, PIWI-interacting RNA, and circular RNA in human saliva. Clin. Chem. 61:1221–30 [Google Scholar]
  17. Bai X, Fischer S, Keshavjee S, Liu M. 17.  2000. Heparin interference with reverse transcriptase polymerase chain reaction of RNA extracted from lungs after ischemia-reperfusion. Transpl. Int. 13:2146–50 [Google Scholar]
  18. Baier SR. 18.  2015. MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow's milk and chicken eggs and affect gene expression in peripheral blood mononuclear cells, cell cultures, and mouse livers. PhD Thesis, Univ. Neb., Linc. http://digitalcommons.unl.edu/nutritiondiss/50
  19. Baier SR, Nguyen C, Xie F, Wood JR, Zempleni J. 19.  2014. MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells, HEK-293 kidney cell cultures, and mouse livers. J. Nutr. 144:101495–500 [Google Scholar]
  20. Bala S, Petrasek J, Mundkur S, Catalano D, Levin I. 20.  et al. 2012. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology 56:51946–57 [Google Scholar]
  21. Batagov AO, Kurochkin IV. 21.  2013. Exosomes secreted by human cells transport largely mRNA fragments that are enriched in the 3′-untranslated regions. Biol. Direct. 8:12 [Google Scholar]
  22. Beatty M, Guduric-Fuchs J, Brown E, Bridgett S, Chakravarthy U. 22.  et al. 2014. Small RNAs from plants, bacteria and fungi within the order Hypocreales are ubiquitous in human plasma. BMC Genom. 15:933 [Google Scholar]
  23. Beckett EL, Martin C, Duesing K, Jones P, Furst J. 23.  et al. 2014. Vitamin D receptor genotype modulates the correlation between vitamin D and circulating levels of let-7a/b and vitamin D intake in an elderly cohort. J. Nutrigenetics Nutrigenomics 7:4–6264–73 [Google Scholar]
  24. Biller SJ, Schubotz F, Roggensack SE, Thompson AW, Summons RE, Chisholm SW. 24.  2014. Bacterial vesicles in marine ecosystems. Science 343:6167183–86 [Google Scholar]
  25. Boeckel J-N, Thomé CE, Leistner D, Zeiher AM, Fichtlscherer S, Dimmeler S. 25.  2013. Heparin selectively affects the quantification of microRNAs in human blood samples. Clin. Chem. 59:71125–27 [Google Scholar]
  26. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y. 26.  et al. 2014. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159:3499–513 [Google Scholar]
  27. Bomberger JM, Maceachran DP, Coutermarsh B, Ye S, O'Toole G, Stanton B. 27.  2009. Long-distance delivery of bacterial virulence factors by Pseudomonas aeruginosa outer membrane vesicles. PLOS Pathog. 5:4e1000382 [Google Scholar]
  28. Braun RE, Behringer RR, Peschon JJ, Brinster RL, Palmiter RD. 28.  1989. Genetically haploid spermatids are phenotypically diploid. Nature 337:6205373–76 [Google Scholar]
  29. Brosnan CA, Voinnet O. 29.  2011. Cell-to-cell and long-distance siRNA movement in plants: mechanisms and biological implications. Curr. Opin. Plant Biol. 14:5580–87 [Google Scholar]
  30. Brown L, Wolf JM, Prados-Rosales R, Casadevall A. 30.  2015. Through the wall: extracellular vesicles in gram-positive bacteria, mycobacteria and fungi. Nat. Rev. Microbiol. 13:10620–30 [Google Scholar]
  31. Bryniarski K, Ptak W, Martin E, Nazimek K, Szczepanik M. 31.  et al. 2015. Free extracellular miRNA functionally targets cells by transfecting exosomes from their companion cells. PLOS ONE 10:4e0122991 [Google Scholar]
  32. Bryzgunova OE, Laktionov PP. 32.  2015. Extracellular nucleic acids in urine: sources, structure, diagnostic potential. Acta Nat. 7:348–54 [Google Scholar]
  33. Buck AH, Coakley G, Simbari F, McSorley HJ, Quintana JF. 33.  et al. 2014. Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity. Nat. Commun. 5:5488 [Google Scholar]
  34. Burroughs AM, Ando Y, de Hoon MJL, Tomaru Y, Suzuki H. 34.  et al. Deep-sequencing of human Argonaute-associated small RNAs provides insight into miRNA sorting and reveals Argonaute association with RNA fragments of diverse origin. RNA Biol. 8:1158–77 [Google Scholar]
  35. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J. 35.  et al. 2009. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 55:4611–22 [Google Scholar]
  36. Bye A, Røsjø H, Aspenes ST, Condorelli G, Omland T, Wisløff U. 36.  2013. Circulating microRNAs and aerobic fitness—the HUNT-study. PLOS ONE 8:2e57496 [Google Scholar]
  37. Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. 37.  2015. Dysbiosis of the gut microbiota in disease. Microb. Ecol. Health Dis. 26:26191 [Google Scholar]
  38. Carthew RW, Sontheimer EJ. 38.  2009. Origins and mechanisms of miRNAs and siRNAs. Cell 136:4642–55 [Google Scholar]
  39. Chahar HS, Bao X, Casola A. 39.  2015. Exosomes and their role in the life cycle and pathogenesis of RNA viruses. Viruses 7:63204–25 [Google Scholar]
  40. Chakrabortty SK, Prakash A, Nechooshtan G, Hearn S, Gingeras TR. 40.  2015. Extracellular vesicle-mediated transfer of processed and functional RNY5 RNA. RNA 21:111966–79 [Google Scholar]
  41. Chen X, Ba Y, Ma L, Cai X, Yin Y. 41.  et al. 2008. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 18:10997–1006 [Google Scholar]
  42. Chen X, Liang H, Zhang J, Zen K, Zhang C-Y. 42.  2013. MicroRNAs are ligands of Toll-like receptors. RNA 19:6737–39 [Google Scholar]
  43. Cheng G, Luo R, Hu C, Cao J, Jin Y. 43.  2013. Deep sequencing-based identification of pathogen-specific microRNAs in the plasma of rabbits infected with Schistosoma japonicum. Parasitology 140:141751–61 [Google Scholar]
  44. Chevillet JR, Kang Q, Ruf IK, Briggs HA, Vojtech LN. 44.  et al. 2014. Quantitative and stoichiometric analysis of the microRNA content of exosomes. PNAS 111:4114888–93 [Google Scholar]
  45. Chiantia S, Kahya N, Ries J, Schwille P. 45.  2006. Effects of ceramide on liquid-ordered domains investigated by simultaneous AFM and FCS. Biophys. J. 90:124500–8 [Google Scholar]
  46. Chim SS, Shing TK, Hung EC, Leung T-Y, Lau T-K. 46.  et al. 2008. Detection and characterization of placental microRNAs in maternal plasma. Clin. Chem. 54:3482–90 [Google Scholar]
  47. Cocucci E, Racchetti G, Meldolesi J. 47.  2009. Shedding microvesicles: artefacts no more. Trends Cell Biol. 19:243–51 [Google Scholar]
  48. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE. 48.  et al. 2014. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:7484559–63 [Google Scholar]
  49. De Boer HC, van Solingen C, Prins J, Duijs JM, Huisman MV. 49.  et al. 2013. Aspirin treatment hampers the use of plasma microRNA-126 as a biomarker for the progression of vascular disease. Eur. Heart J. 34:443451–57 [Google Scholar]
  50. De Maio A. 50.  2011. Extracellular heat shock proteins, cellular export vesicles, and the Stress Observation System: a form of communication during injury, infection, and cell damage. It is never known how far a controversial finding will go! Dedicated to Ferruccio Ritossa. Cell Stress Chaperones 16:3235–49 [Google Scholar]
  51. Dhahbi JM, Spindler SR. 51.  2013. 5′-YRNA fragments derived by processing of transcripts from specific YRNA genes and pseudogenes are abundant in human serum and plasma. Physiol. Genom. 45:21990–98 [Google Scholar]
  52. Dhahbi JM, Spindler SR, Atamna H, Boffelli D, Martin DI. 52.  2014. Deep sequencing of serum small RNAs identifies patterns of 5′ tRNA half and YRNA fragment expression associated with breast cancer. Biomark. Cancer 6:37–47 [Google Scholar]
  53. Dhahbi JM, Spindler SR, Atamna H, Yamakawa A, Boffelli D. 53.  et al. 2013. 5′ tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction. BMC Genom. 14:298 [Google Scholar]
  54. Dickinson B, Zhang Y, Petrick JS, Heck G, Ivashuta S, Marshall WS. 54.  2013. Lack of detectable oral bioavailability of plant microRNAs after feeding in mice. Nat. Biotechnol. 31:11965–67 [Google Scholar]
  55. Duxbury MS, Ashley SW, Whang EE. 55.  2005. RNA interference: a mammalian SID-1 homologue enhances siRNA uptake and gene silencing efficacy in human cells. Biochem. Biophys. Res. Commun. 331:2459–63 [Google Scholar]
  56. Ekström K, Valadi H, Sjöstrand M, Malmhäll C, Bossios A. 56.  et al. 2012. Characterization of mRNA and microRNA in human mast cell-derived exosomes and their transfer to other mast cells and blood CD34 progenitor cells. J. Extracell. Vesicles 1:18389 [Google Scholar]
  57. Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ. 57.  1998. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J. Biol. Chem. 273:3220121–27 [Google Scholar]
  58. Etheridge A, Lee I, Hood L, Galas D, Wang K. 58.  2011. Extracellular microRNA: a new source of biomarkers. Mutat. Res. 717:1–285–90 [Google Scholar]
  59. Fabbri M, Paone A, Calore F, Galli R, Gaudio E. 59.  et al. 2012. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. PNAS 109:31E2110–16 [Google Scholar]
  60. Feinberg EH, Hunter CP. 60.  2003. Transport of dsRNA into cells by the transmembrane protein SID-1. Science 301:56391545–47 [Google Scholar]
  61. Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A. 61.  et al. 2010. Circulating microRNAs in patients with coronary artery disease. Circ. Res. 107:5677–84 [Google Scholar]
  62. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. 62.  1998. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:6669806–11 [Google Scholar]
  63. Fritz JV. 63.  2015. Extracellular RNA in bacteria. exRNA Research Portal Bethesda, MD: US NIH. http://exrna.org/extracellular-rna-bacteria/ [Google Scholar]
  64. Fu X-D. 64.  2014. Non-coding RNA: a new frontier in regulatory biology. Natl. Sci. Rev. 1:2190–204 [Google Scholar]
  65. Fuchs RT, Sun Z, Zhuang F, Robb GB. 65.  2015. Bias in ligation-based small RNA sequencing library construction is determined by adaptor and RNA structure. PLOS ONE 10:5e0126049 [Google Scholar]
  66. García ME, Blanco JL, Caballero J, Gargallo-Viola D. 66.  2002. Anticoagulants interfere with PCR used to diagnose invasive aspergillosis. J. Clin. Microbiol. 40:41567–68 [Google Scholar]
  67. Garcia-Silva MR, das Neves R, Cabrera-Cabrera F, Sanguinetti J, Medeiros LC. 67.  et al. 2014. Extracellular vesicles shed by Trypanosoma cruzi are linked to small RNA pathways, life cycle regulation, and susceptibility to infection of mammalian cells. Parasitol. Res. 113:1285–304 [Google Scholar]
  68. Gebetsberger J, Polacek N. 68.  2013. Slicing tRNA to boost functional ncRNA diversity. RNA Biol. 10:121798–806 [Google Scholar]
  69. Ghosal A, Upadhyaya BB, Fritz JV, Heintz-Buschart A, Desai MS. 69.  et al. 2015. The extracellular RNA complement of Escherichia coli. Microbiol. Open 4:2252–66 [Google Scholar]
  70. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. 70.  2009. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat. Cell Biol. 11:91143–49 [Google Scholar]
  71. Grant R, Ansa-Addo E, Stratton D, Antwi-Baffour S, Jorfi S. 71.  et al. 2011. A filtration-based protocol to isolate human plasma membrane-derived vesicles and exosomes from blood plasma. J. Immunol. Methods 371:1–2143–51 [Google Scholar]
  72. Groschwitz KR, Hogan SP. 72.  2009. Intestinal barrier function: molecular regulation and disease pathogenesis. J. Allergy Clin. Immunol. 124:13–20 [Google Scholar]
  73. Guduric-Fuchs J, O'Connor A, Camp B, O'Neill CL, Medina RJ, Simpson DA. 73.  2012. Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types. BMC Genom. 13:357 [Google Scholar]
  74. Guduric-Fuchs J, O'Connor A, Cullen A, Harwood L, Medina RJ. 74.  et al. 2012. Deep sequencing reveals predominant expression of miR-21 amongst the small non-coding RNAs in retinal microvascular endothelial cells. J. Cell. Biochem. 113:62098–111 [Google Scholar]
  75. Hafner M, Renwick N, Brown M, Mihailović A, Holoch D. 75.  et al. 2011. RNA-ligase-dependent biases in miRNA representation in deep-sequenced small RNA cDNA libraries. RNA 17:91697–712 [Google Scholar]
  76. Halkein J, Tabruyn SP, Ricke-Hoch M, Haghikia A, Nguyen N-Q-N. 76.  et al. 2013. MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J. Clin. Investig. 123:52143–54 [Google Scholar]
  77. Haussecker D, Huang Y, Lau A, Parameswaran P, Fire AZ, Kay MA. 77.  2010. Human tRNA-derived small RNAs in the global regulation of RNA silencing. RNA 16:4673–95 [Google Scholar]
  78. Hebels DG, van Herwijnen MH, Brauers KJ, de Kok TM, Chalkiadaki G. 78.  et al. 2014. Elimination of heparin interference during microarray processing of fresh and biobank-archived blood samples. Environ. Mol. Mutagen. 55:6482–91 [Google Scholar]
  79. Hindson CM, Chevillet JR, Briggs HA, Gallichotte EN, Ruf IK. 79.  et al. 2013. Absolute quantification by droplet digital PCR versus analog real-time PCR. Nat. Methods 10:101003–5 [Google Scholar]
  80. Hollingsworth MA, Swanson BJ. 80.  2004. Mucins in cancer: protection and control of the cell surface. Nat. Rev. Cancer 4:145–60 [Google Scholar]
  81. Hooper LV, Littman DR, Macpherson AJ. 81.  2012. Interactions between the microbiota and the immune system. Science 336:60861268–73 [Google Scholar]
  82. Ismail N, Wang Y, Dakhlallah D, Moldovan L, Agarwal K. 82.  et al. 2013. Macrophage microvesicles induce macrophage differentiation and miR-223 transfer. Blood 121:6984–95 [Google Scholar]
  83. Ivanov P, Emara MM, Villen J, Gygi SP, Anderson P. 83.  2011. Angiogenin-induced tRNA fragments inhibit translation initiation. Mol. Cell 43:4613–23 [Google Scholar]
  84. Iwasaki YW, Siomi MC, Siomi H. 84.  2015. PIWI-interacting RNA: its biogenesis and functions. Annu. Rev. Biochem. 84:405–33 [Google Scholar]
  85. Jakymiw A, Pauley KM, Li S, Ikeda K, Lian S. 85.  et al. 2007. The role of GW/P-bodies in RNA processing and silencing. J. Cell Sci. 120:Pt 81317–23 [Google Scholar]
  86. Janas T, Janas MM, Sapoń K, Janas T. 86.  2015. Mechanisms of RNA loading into exosomes. FEBS Lett. 589:1391–98 [Google Scholar]
  87. Janas T, Janas T, Yarus M. 87.  2006. Specific RNA binding to ordered phospholipid bilayers. Nucleic Acids Res. 34:72128–36 [Google Scholar]
  88. Jayaprakash AD, Jabado O, Brown BD, Sachidanandam R. 88.  2011. Identification and remediation of biases in the activity of RNA ligases in small-RNA deep sequencing. Nucleic Acids Res. 39:21e141 [Google Scholar]
  89. 89.  Deleted in proof
  90. Jiang Q, Wang Y, Hao Y, Juan L, Teng M. 90.  et al. 2009. miR2Disease: a manually curated database for microRNA deregulation in human disease. Nucleic Acids Res. 37:Suppl. 1D98–104 [Google Scholar]
  91. Jose AM, Garcia GA, Hunter CP. 91.  2011. Two classes of silencing RNAs move between Caenorhabditis elegans tissues. Nat. Struct. Mol. Biol. 18:111184–88 [Google Scholar]
  92. Kamath RS, Fraser AG, Dong Y, Poulin G, Durbin R. 92.  et al. 2003. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421:6920231–37 [Google Scholar]
  93. Karere GM, Glenn JP, VandeBerg JL, Cox LA. 93.  2012. Differential microRNA response to a high-cholesterol, high-fat diet in livers of low and high LDL-C baboons. BMC Genom. 13:320 [Google Scholar]
  94. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. 94.  2011. Human nutrition, the gut microbiome and the immune system. Nature 474:7351327–36 [Google Scholar]
  95. Kirschner MB, Kao SC, Edelman JJ, Armstrong NJ, Vallely MP. 95.  et al. 2011. Haemolysis during sample preparation alters microRNA content of plasma. PLOS ONE 6:9e24145 [Google Scholar]
  96. Kirschner MB, van Zandwijk N, Reid G. 96.  2013. Cell-free microRNAs: potential biomarkers in need of standardized reporting. Front. Genet. 4:56 [Google Scholar]
  97. Knip M, Constantin ME, Thordal-Christensen H. 97.  2014. Trans-kingdom cross-talk: small RNAs on the move. PLOS Genet. 10:9e1004602 [Google Scholar]
  98. Kogure T, Lin W-L, Yan IK, Braconi C, Patel T. 98.  2011. Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology 54:41237–48 [Google Scholar]
  99. Kogure T, Yan IK, Lin W-L, Patel T. 99.  2013. Extracellular vesicle-mediated transfer of a novel long noncoding RNA TUC339: a mechanism of intercellular signaling in human hepatocellular cancer. Genes Cancer 4:7–8261–72 [Google Scholar]
  100. Koppers-Lalic D, Hackenberg M, Bijnsdorp I, van Eijndhoven M, Sadek P. 100.  et al. 2014. Non-templated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep. 8:61649–58 [Google Scholar]
  101. Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T. 101.  2013. Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J. Biol. Chem. 288:1510849–59 [Google Scholar]
  102. Kosaka N, Iguchi H, Ochiya T. 102.  2010. Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci. 101:102087–92 [Google Scholar]
  103. Kosaka N, Iguchi H, Yoshioka Y, Hagiwara K, Takeshita F, Ochiya T. 103.  2012. Competitive interactions of cancer cells and normal cells via secretory microRNAs. J. Biol. Chem. 287:21397–405 [Google Scholar]
  104. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. 104.  2010. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J. Biol. Chem. 285:2317442–52 [Google Scholar]
  105. Kosaka N, Izumi H, Sekine K, Ochiya T. 105.  2010. MicroRNA as a new immune-regulatory agent in breast milk. Silence 1:17 [Google Scholar]
  106. Kroh EM, Parkin RK, Mitchell PS, Tewari M. 106.  2010. Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods 50:4298–301 [Google Scholar]
  107. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. 107.  2002. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12:9735–39 [Google Scholar]
  108. Lara PC, Pruschy M, Zimmermann M, Henríquez-Hernández LA. 108.  2011. MVP and vaults: a role in the radiation response. Radiat. Oncol. 6:148 [Google Scholar]
  109. Lasda E, Parker R. 109.  2014. Circular RNAs: diversity of form and function. RNA 20:121829–42 [Google Scholar]
  110. Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP. 110.  et al. 2008. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br. J. Haematol. 141:5672–75 [Google Scholar]
  111. Lee LW, Zhang S, Etheridge A, Ma L, Martin D. 111.  et al. 2010. Complexity of the microRNA repertoire revealed by next-generation sequencing. RNA 16:112170–80 [Google Scholar]
  112. Lee YJ, Kim V, Muth DC, Witwer KW. 111a.  2015. Validated microRNA target databases: an evaluation. Drug Dev. Res 76:7389–96 [Google Scholar]
  113. Lehmann SM, Krüger C, Park B, Derkow K, Rosenberger K. 112.  et al. 2012. An unconventional role for miRNA: Let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat. Neurosci. 15:6827–35 [Google Scholar]
  114. Leidner RS, Li L, Thompson CL. 113.  2013. Dampening enthusiasm for circulating microRNA in breast cancer. PLOS ONE 8:3e57841 [Google Scholar]
  115. Li Y, Qiu C, Tu J, Geng B, Yang J. 114.  et al. 2014. HMDD v2.0: a database for experimentally supported human microRNA and disease associations. Nucleic Acids Res. 42:Suppl. 1D1070–74 [Google Scholar]
  116. Li Z, Ender C, Meister G, Moore PS, Chang Y, John B. 115.  2012. Extensive terminal and asymmetric processing of small RNAs from rRNAs, snoRNAs, snRNAs, and tRNAs. Nucleic Acids Res. 40:146787–99 [Google Scholar]
  117. Liang H, Zhang S, Fu Z, Wang Y, Wang N. 116.  et al. 2015. Effective detection and quantification of dietetically absorbed plant microRNAs in human plasma. J. Nutr. Biochem. 26:5505–12 [Google Scholar]
  118. Lim PK, Bliss SA, Patel SA, Taborga M, Dave MA. 117.  et al. 2011. Gap junction-mediated import of microRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. Cancer Res. 71:51550–60 [Google Scholar]
  119. Liu H, Wang X, Wang H-D, Wu J, Ren J. 118.  et al. 2012. Escherichia coli noncoding RNAs can affect gene expression and physiology of Caenorhabditis elegans. Nat. Commun. 3:1073 [Google Scholar]
  120. Liu S, da Cunha AP, Rezende RM, Cialic R, Wei Z. 119.  et al. 2016. The host shapes the gut microbiota via fecal microRNA. Cell Host Microbe 19:132–43 [Google Scholar]
  121. Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC. 120.  et al. 2006. Transforming growth factor-β induces development of the TH17 lineage. Nature 441:7090231–34 [Google Scholar]
  122. Mao Y-B, Xue X-Y, Tao X-Y, Yang C-Q, Wang L-J, Chen X-Y. 121.  2013. Cysteine protease enhances plant-mediated bollworm RNA interference. Plant Mol. Biol. 83:1–2119–29 [Google Scholar]
  123. Martí E, Pantano L, Bañez-Coronel M, Llorens F, Miñones-Moyano E. 122.  et al. 2010. A myriad of miRNA variants in control and Huntington's disease brain regions detected by massively parallel sequencing. Nucleic Acids Res. 38:207219–35 [Google Scholar]
  124. Marz M, Gruber AR, Höner zu Siederdissen C, Amman F, Badelt S. 123.  et al. 2011. Animal snoRNAs and scaRNAs with exceptional structures. RNA Biol. 8:6938–46 [Google Scholar]
  125. Meckes DG, Shair KHY, Marquitz AR, Kung C-P, Edwards RH, Raab-Traub N. 124.  2010. Human tumor virus utilizes exosomes for intercellular communication. PNAS 107:4720370–75 [Google Scholar]
  126. Melnik BC. 125.  2015. Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases. J. Transl. Med. 13:1385 [Google Scholar]
  127. Mishima E, Inoue C, Saigusa D, Inoue R, Ito K. 126.  et al. 2014. Conformational change in transfer RNA is an early indicator of acute cellular damage. J. Am. Soc. Nephrol. 25:102316–26 [Google Scholar]
  128. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK. 127.  et al. 2008. Circulating microRNAs as stable blood-based markers for cancer detection. PNAS 105:3010513–18 [Google Scholar]
  129. Mittelbrunn M, Gutiérrez-Vázquez C, Villarroya-Beltri C, González S, Sánchez-Cabo F. 128.  et al. 2011. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2:282 [Google Scholar]
  130. Mittelbrunn M, Sánchez-Madrid F. 129.  2012. Intercellular communication: diverse structures for exchange of genetic information. Nat. Rev. Mol. Cell Biol. 13:5328–35 [Google Scholar]
  131. Mlotshwa S, Pruss GJ, MacArthur JL, Endres MW, Davis C. 130.  et al. 2015. A novel chemopreventive strategy based on therapeutic microRNAs produced in plants. Cell Res. 25:4521–24 [Google Scholar]
  132. Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan MLG. 131.  et al. 2012. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:3756–66 [Google Scholar]
  133. Morel L, Regan M, Higashimori H, Ng SK, Esau C. 132.  et al. 2013. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J. Biol. Chem. 288:107105–16 [Google Scholar]
  134. Mulcahy LA, Pink RC, Carter DRF. 133.  2014. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 3:3 [Google Scholar]
  135. Munafó DB, Robb GB. 134.  2010. Optimization of enzymatic reaction conditions for generating representative pools of cDNA from small RNA. RNA 16:122537–52 [Google Scholar]
  136. Narayanan A, Iordanskiy S, Das R, Van Duyne R, Santos S. 135.  et al. 2013. Exosomes derived from HIV-1-infected cells contain trans-activation response element RNA. J. Biol. Chem. 288:2720014–33 [Google Scholar]
  137. Nguyen VT, Kiss T, Michels AA, Bensaude O. 136.  2001. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 414:6861322–25 [Google Scholar]
  138. Nicola AM, Frases S, Casadevall A. 137.  2009. Lipophilic dye staining of Cryptococcus neoformans extracellular vesicles and capsule. Eukaryot. Cell 8:91373–80 [Google Scholar]
  139. 138. NIH (Natl. Inst. Health). 2016. Extracellular RNA Communication Consortium Bethesda, MD: US NIH. http://exrna.org/
  140. Nolte-'t Hoen EN, Buermans HP, Waasdorp M, Stoorvogel W, Wauben MH, 't Hoen PA. 139.  2012. Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions. Nucleic Acids Res. 40:189272–85 [Google Scholar]
  141. Obregón-Henao A, Duque-Correa M, Rojas M, García LF, Brennan PJ. 140.  et al. 2012. Stable extracellular RNA fragments of Mycobacterium tuberculosis induce early apoptosis in human monocytes via a caspase-8 dependent mechanism. PLOS ONE 7:1e29970 [Google Scholar]
  142. Oldenburg M, Krüger A, Ferstl R, Kaufmann A, Nees G. 141.  et al. 2012. TLR13 recognizes bacterial 23s rRNA devoid of erythromycin resistance-forming modification. Science 337:60981111–15 [Google Scholar]
  143. Oliveira DL, Freire-de-Lima CG, Nosanchuk JD, Casadevall A, Rodrigues ML, Nimrichter L. 142.  2010. Extracellular vesicles from Cryptococcus neoformans modulate macrophage functions. Infect. Immun. 78:41601–9 [Google Scholar]
  144. Page K, Guttery DS, Zahra N, Primrose L, Elshaw SR. 143.  et al. 2013. Influence of plasma processing on recovery and analysis of circulating nucleic acids. PLOS ONE 8:10e77963 [Google Scholar]
  145. Park K-S, Choi K-H, Kim Y-S, Hong BS, Kim OY. 144.  et al. 2010. Outer membrane vesicles derived from Escherichia coli induce systemic inflammatory response syndrome. PLOS ONE 5:6e11334 [Google Scholar]
  146. Parker H, Chitcholtan K, Hampton MB, Keenan JI. 145.  2010. Uptake of Helicobacter pylori outer membrane vesicles by gastric epithelial cells. Infect. Immun. 78:125054–61 [Google Scholar]
  147. Patton JG, Franklin JL, Weaver AM, Vickers K, Zhang B. 146.  et al. 2015. Biogenesis, delivery, and function of extracellular RNA. J. Extracell. Vesicles 1:27494 [Google Scholar]
  148. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES. 147.  et al. 2010. Functional delivery of viral miRNAs via exosomes. PNAS 107:146328–33 [Google Scholar]
  149. Peres da Silva R, Puccia R, Rodrigues ML, Oliveira DL, Joffe LS. 148.  et al. 2015. Extracellular vesicle-mediated export of fungal RNA. Sci. Rep. 5:7763 [Google Scholar]
  150. Plieskatt JL, Feng Y, Rinaldi G, Mulvenna JP, Bethony JM, Brindley PJ. 149.  2014. Circumventing qPCR inhibition to amplify miRNAs in plasma. Biomark. Res. 2:13 [Google Scholar]
  151. Puppa MJ, White JP, Sato S, Cairns M, Baynes JW, Carson JA. 150.  2011. Gut barrier dysfunction in the APCMin/+ mouse model of colon cancer cachexia. Biochim. Biophys. Acta. 1812:121601–6 [Google Scholar]
  152. Quinn JF, Patel T, Wong D, Das S, Freedman JE. 151.  et al. 2015. Extracellular RNAs: development as biomarkers of human disease. J. Extracell. Vesicles 4:27495 [Google Scholar]
  153. Quintana JF, Makepeace BL, Babayan SA, Ivens A, Pfarr KM. 152.  et al. 2015. Extracellular onchocerca-derived small RNAs in host nodules and blood. Parasites Vectors 8:58 [Google Scholar]
  154. Raposo G, Stoorvogel W. 153.  2013. Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200:4373–83 [Google Scholar]
  155. Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R. 154.  et al. 2006. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20:5847–56 [Google Scholar]
  156. Rekker K, Saare M, Roost AM, Kubo A-L, Zarovni N. 155.  et al. 2014. Comparison of serum exosome isolation methods for microRNA profiling. Clin. Biochem. 47:1–2135–38 [Google Scholar]
  157. Resnick KE, Alder H, Hagan JP, Richardson DL, Croce CM, Cohn DE. 156.  2009. The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Gynecol. Oncol. 112:155–59 [Google Scholar]
  158. Ridder K, Keller S, Dams M, Rupp A-K, Schlaudraff J. 157.  et al. 2014. Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation. PLOS Biol. 12:6e1001874 [Google Scholar]
  159. Risso D, Ngai J, Speed TP, Dudoit S. 158.  2014. Normalization of RNA-seq data using factor analysis of control genes or samples. Nat. Biotechnol. 32:9896–902 [Google Scholar]
  160. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW. 159.  et al. 2015. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43:7e47 [Google Scholar]
  161. Rome S. 160.  2015. Use of miRNAs in biofluids as biomarkers in dietary and lifestyle intervention studies. Genes Nutr. 10:533 [Google Scholar]
  162. Romilly C, Lays C, Tomasini A, Caldelari I, Benito Y. 161.  et al. 2014. A non-coding RNA promotes bacterial persistence and decreases virulence by regulating a regulator in Staphylococcus aureus. PLOS Pathog. 10:3e1003979 [Google Scholar]
  163. Rosa A, Brivanlou AH. 162.  2009. MicroRNAs in early vertebrate development. Cell Cycle 8:213513–20 [Google Scholar]
  164. Rosenblad MA, Larsen N, Samuelsson T, Zwieb C. 163.  2014. Kinship in the SRP RNA family. RNA Biol. 6:5508–16 [Google Scholar]
  165. Roume H, Muller EEL, Cordes T, Renaut J, Hiller K, Wilmes P. 164.  2013. A biomolecular isolation framework for eco-systems biology. ISME J. 7:1110–21 [Google Scholar]
  166. Russo F. 165.  2015. miRandola database: the future of non-invasive diagnosis through circulating RNA biomarkers. Extracellular RNA Communication Consortium Bethesda, MD: US NIH. http://exrna.org/miran-dola-database-the-future-of-non-invasive-diagnosis-through-circulating-rna-biomarkers/ [Google Scholar]
  167. Ryu M-S, Langkamp-Henken B, Chang S-M, Shankar MN, Cousins RJ. 166.  2011. Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis. PNAS 108:5220970–75 [Google Scholar]
  168. Salter SJ, Cox MJ, Turek EM, Calus ST, Cookson WO. 167.  et al. 2014. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. 12:187 [Google Scholar]
  169. Samson JE, Magadán AH, Sabri M, Moineau S. 168.  2013. Revenge of the phages: defeating bacterial defences. Nat. Rev. Microbiol. 11:10675–87 [Google Scholar]
  170. Sana J, Faltejskova P, Svoboda M, Slaby O. 169.  2012. Novel classes of non-coding RNAs and cancer. J. Transl. Med. 10:1103 [Google Scholar]
  171. Sato-Kuwabara Y, Melo SA, Soares FA, Calin GA. 170.  2014. The fusion of two worlds: non-coding RNAs and extracellular vesicles—diagnostic and therapeutic implications (Review). Int. J. Oncol. 46:117–27 [Google Scholar]
  172. Schwechheimer C, Kuehn MJ. 171.  2015. Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat. Rev. Microbiol. 13:10605–19 [Google Scholar]
  173. Semenov D V, Baryakin DN, Brenner E V, Kurilshikov AM, Vasiliev GV. 172.  et al. 2012. Unbiased approach to profile the variety of small non-coding RNA of human blood plasma with massively parallel sequencing technology. Expert Opin. Biol. Ther. 12:Suppl. 1S43–51 [Google Scholar]
  174. Sewer A, Gubian S, Kogel U, Veljkovic E, Han W. 173.  et al. 2014. Assessment of a novel multi-array normalization method based on spike-in control probes suitable for microRNA datasets with global decreases in expression. BMC Res. Notes 7:302 [Google Scholar]
  175. Shao Y, Feng L, Rutherford ST, Papenfort K, Bassler BL. 174.  2013. Functional determinants of the quorum-sensing non-coding RNAs and their roles in target regulation. EMBO J. 32:152158–71 [Google Scholar]
  176. Sharifpanah F, Jayarathne SWG, Bekhite MM, Hurtado-Oliveros J, Preissner KT. 175.  et al. 2015. Stimulation of vasculogenesis and leukopoiesis of embryonic stem cells by extracellular transfer RNA and ribosomal RNA. Free Radic. Biol. Med. 89:1203–17 [Google Scholar]
  177. Shen J, Stass SA, Jiang F. 176.  2013. MicroRNAs as potential biomarkers in human solid tumors. Cancer Lett. 329:2125–36 [Google Scholar]
  178. Shen Y, Giardino Torchia ML, Lawson GW, Karp CL, Ashwell JD, Mazmanian SK. 177.  2012. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12:4509–20 [Google Scholar]
  179. Shih JD, Hunter CP. 178.  2011. SID-1 is a dsRNA-selective dsRNA-gated channel. RNA 17:61057–65 [Google Scholar]
  180. Skog J, Wurdinger T, Rijn SV, Meijer D, Gainche L. 179.  et al. 2012. Glioblastoma microvesicles transport RNA and protein that promote tumor growth and provide diagnostic biomarkers. Nat. Cell Biol. 10:121470–76 [Google Scholar]
  181. Snow JW, Hale AE, Isaacs SK, Baggish AL, Chan SY. 180.  2013. Ineffective delivery of diet-derived microRNAs to recipient animal organisms. RNA Biol. 10:71107–16 [Google Scholar]
  182. Sobala A, Hutvagner G. 181.  2013. Small RNAs derived from the 5′ end of tRNA can inhibit protein translation in human cells. RNA Biol. 10:4553–63 [Google Scholar]
  183. Squadrito ML, Baer C, Burdet F, Maderna C, Gilfillan GD. 182.  et al. 2014. Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep. 8:1432–46 [Google Scholar]
  184. Tabet F, Vickers KC, Cuesta-Torres LF, Wiese Carrie B, Shoucri BM. 183.  et al. 2012. HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells. Nat. Commun. 29:6997–1003 [Google Scholar]
  185. Tarallo S, Pardini B, Mancuso G, Rosa F, Di Gaetano C. 184.  et al. 2014. MicroRNA expression in relation to different dietary habits: a comparison in stool and plasma samples. Mutagenesis 29:5385–91 [Google Scholar]
  186. Théry C, Ostrowski M, Segura E. 185.  2009. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 9:8581–93 [Google Scholar]
  187. Title AC, Denzler R, Stoffel M. 186.  2015. Uptake and function studies of maternal milk-derived microRNAs. J. Biol. Chem. 290:3923680–91 [Google Scholar]
  188. Tosar JP, Gambaro F, Sanguinetti J, Bonilla B, Witwer KW, Cayota A. 187.  2015. Assessment of small RNAsorting into different extracellular fractions revealed by high-throughput sequencing of breast cell lines. Nucleic Acids Res. 43:115601–16 [Google Scholar]
  189. Trapnell C, Hendrickson DG, Sauvageau M, Goff L, Rinn JL, Pachter L. 188.  2013. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat. Biotechnol. 31:146–53 [Google Scholar]
  190. Tsui NB, Ng EK, Lo YM. 189.  2002. Stability of endogenous and added RNA in blood specimens, serum, and plasma. Clin. Chem. 48:101647–53 [Google Scholar]
  191. Tsuji E, Hiki N, Nomura S, Fukushima R, Kojima J. 190.  et al. 2003. Simultaneous onset of acute inflammatory response, sepsis-like symptoms and intestinal mucosal injury after cancer chemotherapy. Int. J. Cancer. 107:2303–8 [Google Scholar]
  192. Turchinovich A, Samatov TR, Tonevitsky AG, Burwinkel B. 191.  2013. Circulating miRNAs: cell–cell communication function?. Front. Genet. 4:119 [Google Scholar]
  193. Turchinovich A, Weiz L, Burwinkel B. 192.  2012. Extracellular miRNAs: the mystery of their origin and function. Trends Biochem. Sci. 37:11460–65 [Google Scholar]
  194. Turchinovich A, Weiz L, Langheinz A, Burwinkel B. 193.  2011. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 39:167223–33 [Google Scholar]
  195. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. 194.  2007. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9:6654–59 [Google Scholar]
  196. Van Balkom BWM, Eisele AS, Pegtel DM, Bervoets S, Verhaar MC. 195.  2015. Quantitative and qualitative analysis of small RNAs in human endothelial cells and exosomes provides insights into localized RNA processing, degradation and sorting. J. Extracell. Vesicles 4:26760 [Google Scholar]
  197. Van der Pol E, Böing AN, Harrison P, Sturk A, Nieuwland R. 196.  2012. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol. Rev. 64:3676–705 [Google Scholar]
  198. Van Deun J, Mestdagh P, Sormunen R, Cocquyt V, Vermaelen K. 197.  et al. 2014. The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. J. Extracell. Vesicles 3:24858 [Google Scholar]
  199. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. 198.  2011. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13:4423–33 [Google Scholar]
  200. Vickers KC, Roteta LA, Hucheson-Dilks H, Han L, Guo Y. 199.  2015. Mining diverse small RNA species in the deep transcriptome. Trends Biochem. Sci. 40:14–7 [Google Scholar]
  201. Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, Sánchez-Madrid F, Mittelbrunn M. 200.  2014. Sorting it out: regulation of exosome loading. Semin. Cancer Biol. 28:3–13 [Google Scholar]
  202. Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J. 201.  et al. 2013. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4:2980 [Google Scholar]
  203. Voellenkle C, Rooij JV, Guffanti A, Brini E, Fasanaro P. 202.  et al. 2012. Deep-sequencing of endothelial cells exposed to hypoxia reveals the complexity of known and novel microRNAs. RNA 18:3472–84 [Google Scholar]
  204. Wagner J, Riwanto M, Besler C, Knau A, Fichtlscherer S. 203.  et al. 2013. Characterization of levels and cellular transfer of circulating lipoprotein-bound microRNAs. Arterioscler. Thromb. Vasc. Biol. 33:61392–400 [Google Scholar]
  205. Wang H, Li X, Wang C, Zhu D, Xu Y. 204.  2014. Abnormal ultrastructure of intestinal epithelial barrier in mice with alcoholic steatohepatitis. Alcohol 48:8787–93 [Google Scholar]
  206. Wang K, Li H, Yuan Y, Etheridge A, Zhou Y. 205.  et al. 2012. The complex exogenous RNA spectra in human plasma: an interface with human gut biota?. PLOS ONE 7:12e51009 [Google Scholar]
  207. Wang K, Yuan Y, Cho J-H, McClarty S, Baxter D, Galas DJ. 206.  2012. Comparing the microRNA spectrum between serum and plasma. PLOS ONE 7:7e41561 [Google Scholar]
  208. Wang K, Yuan Y, Li H, Cho J-H, Huang D. 207.  et al. 2013. The spectrum of circulating RNA: a window into systems toxicology. Toxicol. Sci. 132:2478–92 [Google Scholar]
  209. Wang K, Zhang S, Marzolf B, Troisch P, Brightman A. 208.  et al. 2009. Circulating microRNAs, potential biomarkers for drug-induced liver injury. PNAS 106:114402–7 [Google Scholar]
  210. Wang K, Zhang S, Weber J, Baxter D, Galas DJ. 209.  2010. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res. 38:207248–59 [Google Scholar]
  211. Wang W, Shi Q, Mattes WB, Mendrick DL, Yang X. 210.  2015. Translating extracellular microRNA into clinical biomarkers for drug-induced toxicity: from high-throughput profiling to validation. Biomark. Med. 9:111177–88 [Google Scholar]
  212. Wang Y, Tong J, Chang B, Wang B, Zhang D, Wang B. 211.  2014. Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction-associated proteins. Mol. Med. Rep 9:62352–56 [Google Scholar]
  213. Wang Y-T, Tsai P-C, Liao Y-C, Hsu C-Y, Juo S-HH. 212.  2013. Circulating microRNAs have a sex-specific association with metabolic syndrome. J. Biomed. Sci. 20:72 [Google Scholar]
  214. Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH. 213.  et al. 2010. The microRNA spectrum in 12 body fluids. Clin. Chem. 56:111733–41 [Google Scholar]
  215. Wild K, Sinning I, Cusack S. 214.  2001. Crystal structure of an early protein–RNA assembly complex of the signal recognition particle. Science 294:5542598–601 [Google Scholar]
  216. Williams Z, Ben-Dov IZ, Elias R, Mihailovic A, Brown M. 215.  et al. 2013. Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations. PNAS 110:114255–60 [Google Scholar]
  217. Winston WM, Molodowitch C, Hunter CP. 216.  2002. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science 295:55642456–59 [Google Scholar]
  218. Witwer KW. 217.  2015. Contamination or artifacts may explain reports of plant miRNAs in humans. J. Nutr. Biochem. 26:121685 [Google Scholar]
  219. Witwer KW. 218.  2015. Circulating microRNA biomarker studies: pitfalls and potential solutions. Clin. Chem. 61:156–63 [Google Scholar]
  220. Witwer KW, Buzás EI, Bemis LT, Bora A, Lässer C. 219.  et al. 2013. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles 2:20360 [Google Scholar]
  221. Witwer KW, Hirschi KD. 220.  2014. Transfer and functional consequences of dietary microRNAs in vertebrates: concepts in search of corroboration. BioEssays 36:4394–406 [Google Scholar]
  222. Witwer KW, McAlexander MA, Queen SE, Adams RJ. 221.  2013. Real-time quantitative PCR and droplet digital PCR for plant miRNAs in mammalian blood provide little evidence for general uptake of dietary miRNAs: limited evidence for general uptake of dietary plant xenomiRs. RNA Biol. 10:71080–86 [Google Scholar]
  223. Wurdinger T, Gatson NN, Balaj L, Kaur B, Breakefield XO, Pegtel DM. 222.  2012. Extracellular vesicles and their convergence with viral pathways. Adv. Virol. 2012:1767694 [Google Scholar]
  224. Xiang S, Fruehauf J, Li CJ. 223.  2006. Short hairpin RNA-expressing bacteria elicit RNA interference in mammals. Nat. Biotechnol. 24:6697–702 [Google Scholar]
  225. Yang J, Farmer LM, Agyekum AA, Hirschi KD. 224.  2015. Detection of dietary plant-based small RNAs in animals. Cell Res. 25:517–20 [Google Scholar]
  226. Yao B, La LB, Chen Y-C, Chang L-J, Chan EKL. 225.  2012. Defining a new role of GW182 in maintaining miRNA stability. EMBO Rep. 13:121102–8 [Google Scholar]
  227. Yarmishyn AA, Kurochkin I V. 226.  2015. Long noncoding RNAs: a potential novel class of cancer biomarkers. Front. Genet. 6:145 [Google Scholar]
  228. Yoo B-C, Kragler F, Varkonyi-Gasic E, Haywood V, Archer-Evans S. 227.  et al. 2004. A systemic small RNA signaling system in plants. Plant Cell 16:81979–2000 [Google Scholar]
  229. Yu B, Yang Z, Li J, Minakhina S, Yang M. 228.  et al. 2005. Methylation as a crucial step in plant microRNA biogenesis. Science 307:5711932–35 [Google Scholar]
  230. Yuan S, Tang H, Xing J, Fan X, Cai X. 229.  et al. 2014. Methylation by NSun2 represses the levels and function of microRNA 125b. Mol. Cell Biol. 34:193630–41 [Google Scholar]
  231. Zempleni J, Baier SR, Hirschi K. 230.  2015. Diet-responsive microRNAs are likely exogenous. J. Biol. Chem. 290:4125197 [Google Scholar]
  232. Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L. 231.  et al. 2009. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal. 2:100ra81 [Google Scholar]
  233. Zhang L, Hou D, Chen X, Li D, Zhu L. 232.  et al. 2012. Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res. 22:1107–26 [Google Scholar]
  234. Zhang Y, Liu D, Chen X, Li J, Li L. 233.  et al. 2010. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 39:1133–44 [Google Scholar]
  235. Zhang Y, Wiggins B, Lawrence C, Petrick J, Ivashuta S, Heck G. 234.  2012. Analysis of plant-derived miRNAs in animal small RNA datasets. BMC Genom. 13:1381 [Google Scholar]
  236. Zhou W, Fong MY, Min Y, Somlo G, Liu L. 235.  et al. 2014. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25:4501–15 [Google Scholar]
  237. Zhou Z, Li X, Liu J, Dong L, Chen Q. 236.  et al. 2014. Honeysuckle-encoded atypical microRNA2911 directly targets influenza A viruses. Cell Res. 25:139–49 [Google Scholar]
  238. Zhu W, Qin W, Atasoy U, Sauter ER. 237.  2009. Circulating microRNAs in breast cancer and healthy subjects. BMC Res. Notes 2:89 [Google Scholar]
  239. Zhuang F, Fuchs RT, Robb GB. 238.  2012. Small RNA expression profiling by high-throughput sequencing: implications of enzymatic manipulation. J. Nucleic Acids 2012:360358 [Google Scholar]
  240. Zhuang F, Fuchs RT, Sun Z, Zheng Y, Robb GB. 239.  2012. Structural bias in T4 RNA ligase-mediated 3′-adapter ligation. Nucleic Acids Res. 40:7e54 [Google Scholar]
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