Extracellular miRNA: A Collision of Two Paradigms.

Since their discovery in 2008, extracellular miRNAs (ex-miRNAs) have persisted as one of the major themes of molecular and cellular biology. The main reason for this remarkable interest is the increasing number of research papers reporting that cell-free circulating miRNA mediates both short-range and distant communication between various cells, and could impact on diverse physiological and pathological processes. However, there are also multiple conflicting lines of evidence that challenge the biological significance of circulating ex-miRNA, suggesting that they are merely byproducts of cell activity and cell death without any particular function. This review aims to summarize these contrasting opinions and to foster further experimental validation of both paradigms.

[1]  M. L. Hastings,et al.  Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells , 2010, PloS one.

[2]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[3]  T. Janas,et al.  Mechanisms of RNA loading into exosomes , 2015, FEBS letters.

[4]  Muneesh Tewari,et al.  Quantitative and stoichiometric analysis of the microRNA content of exosomes , 2014, Proceedings of the National Academy of Sciences.

[5]  Johan Skog,et al.  Glioblastoma microvesicles transport RNA and protein that promote tumor growth and provide diagnostic biomarkers , 2008, Nature Cell Biology.

[6]  Tsutomu Suzuki,et al.  Hsc70/Hsp90 chaperone machinery mediates ATP-dependent RISC loading of small RNA duplexes. , 2010, Molecular cell.

[7]  Roberta Galli,et al.  MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response , 2012, Proceedings of the National Academy of Sciences.

[8]  Xiaoke Yin,et al.  Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. , 2014, The Journal of clinical investigation.

[9]  Mark Ibberson,et al.  Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. , 2014, Cell reports.

[10]  Lianbo Yu,et al.  Detection of microRNA Expression in Human Peripheral Blood Microvesicles , 2008, PloS one.

[11]  T. D. de Gruijl,et al.  Functional delivery of viral miRNAs via exosomes , 2010, Proceedings of the National Academy of Sciences.

[12]  J. M. Thomson,et al.  Argonaute2 Is the Catalytic Engine of Mammalian RNAi , 2004, Science.

[13]  C. Sander,et al.  A Mammalian microRNA Expression Atlas Based on Small RNA Library Sequencing , 2007, Cell.

[14]  V. Kim,et al.  The nuclear RNase III Drosha initiates microRNA processing , 2003, Nature.

[15]  Ryan M. O’Connell,et al.  Exosome-delivered microRNAs modulate the inflammatory response to endotoxin , 2015, Nature Communications.

[16]  R. Malenka,et al.  An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration , 2012, Nature Neuroscience.

[17]  Loyal A Goff,et al.  Differential regulation of microRNA stability. , 2010, RNA.

[18]  Michael T. McManus,et al.  Biogenesis, delivery, and function of extracellular RNA , 2015, Journal of extracellular vesicles.

[19]  X. Chen,et al.  Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases , 2008, Cell Research.

[20]  M. Fabbri.  TLRs as miRNA receptors. , 2012, Cancer research.

[21]  N. Kosaka,et al.  microRNA as a new immune-regulatory agent in breast milk , 2010, Silence.

[22]  B. Ylstra,et al.  Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. , 2014, Cell reports.

[23]  Paul J. Harrison,et al.  Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis , 2011, Nanomedicine : nanotechnology, biology, and medicine.

[24]  Andrew P Lewis,et al.  Regulation and biological function of the liver-specific miR-122. , 2010, Biochemical Society transactions.

[25]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[26]  Barbara Burwinkel,et al.  Distinct AGO1 and AGO2 associated miRNA profiles in human cells and blood plasma , 2012, RNA biology.

[27]  W. Filipowicz,et al.  The widespread regulation of microRNA biogenesis, function and decay , 2010, Nature Reviews Genetics.

[28]  Justin J. Cassidy,et al.  Silencing by small RNAs is linked to endosome trafficking , 2009, Nature Cell Biology.

[29]  Weiying Zhou,et al.  Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. , 2014, Cancer cell.

[30]  S. Akira,et al.  Toll-like receptors. , 2003, Annual review of immunology.

[31]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[32]  R. Gregory,et al.  Many roads to maturity: microRNA biogenesis pathways and their regulation , 2009, Nature Cell Biology.

[33]  Thomas Tuschl,et al.  Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations , 2013, Proceedings of the National Academy of Sciences.

[34]  Jan A Staessen,et al.  Circulating MicroRNA-208b and MicroRNA-499 Reflect Myocardial Damage in Cardiovascular Disease , 2010, Circulation. Cardiovascular genetics.

[35]  B. Burwinkel,et al.  Characterization of extracellular circulating microRNA , 2011, Nucleic acids research.

[36]  F. Sánchez‐Madrid,et al.  Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs , 2013, Nature Communications.

[37]  Yue Wang,et al.  Plasma microRNA-122 as a biomarker for viral-, alcohol-, and chemical-related hepatic diseases. , 2010, Clinical chemistry.

[38]  U. Kutay,et al.  Nuclear Export of MicroRNA Precursors , 2004, Science.

[39]  Fátima Sánchez-Cabo,et al.  Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells , 2011, Nature communications.

[40]  E. Kroh,et al.  Blood Cell Origin of Circulating MicroRNAs: A Cautionary Note for Cancer Biomarker Studies , 2011, Cancer Prevention Research.

[41]  A. Harris,et al.  Detection of elevated levels of tumour‐associated microRNAs in serum of patients with diffuse large B‐cell lymphoma , 2008, British journal of haematology.

[42]  M. Hristov,et al.  Delivery of MicroRNA-126 by Apoptotic Bodies Induces CXCL12-Dependent Vascular Protection , 2009, Science Signaling.

[43]  Sanghyuk Lee,et al.  MicroRNA genes are transcribed by RNA polymerase II , 2004, The EMBO journal.

[44]  T. Tuschl,et al.  Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. , 2004, Molecular cell.

[45]  E. Izaurralde,et al.  Towards a molecular understanding of microRNA-mediated gene silencing , 2015, Nature Reviews Genetics.

[46]  Jessica A. Weber,et al.  Export of microRNAs and microRNA-protective protein by mammalian cells , 2010, Nucleic acids research.

[47]  Margaret S. Ebert,et al.  Roles for MicroRNAs in Conferring Robustness to Biological Processes , 2012, Cell.

[48]  Y. Matsuki,et al.  Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells*♦ , 2010, The Journal of Biological Chemistry.

[49]  Jasmin Wagner,et al.  Characterization of Levels and Cellular Transfer of Circulating Lipoprotein-Bound MicroRNAs , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[50]  K. Vickers,et al.  MicroRNAs are Transported in Plasma and Delivered to Recipient Cells by High-Density Lipoproteins , 2011, Nature Cell Biology.

[51]  Hao Li,et al.  Ago1 Interacts with RNA Polymerase II and Binds to the Promoters of Actively Transcribed Genes in Human Cancer Cells , 2013, PLoS genetics.

[52]  A. O’Connor,et al.  Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types , 2012, BMC Genomics.

[53]  Frank D Sistare,et al.  Plasma MicroRNAs as sensitive and specific biomarkers of tissue injury. , 2009, Clinical chemistry.

[54]  S. Sinha,et al.  Biogenesis of intronic miRNAs located in clusters by independent transcription and alternative splicing , 2014, RNA.

[55]  Ji Wan,et al.  Structure and activity of putative intronic miRNA promoters. , 2010, RNA.

[56]  W. Filipowicz,et al.  Inhibition of Translational Initiation by Let-7 MicroRNA in Human Cells , 2005, Science.

[57]  Isobel S Okoye,et al.  MicroRNA-Containing T-Regulatory-Cell-Derived Exosomes Suppress Pathogenic T Helper 1 Cells , 2014, Immunity.

[58]  R. Shiekhattar,et al.  TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing , 2005, Nature.

[59]  Jing Li,et al.  Secreted monocytic miR-150 enhances targeted endothelial cell migration. , 2010, Molecular cell.

[60]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[61]  T. Leung,et al.  Detection and characterization of placental microRNAs in maternal plasma. , 2008, Clinical chemistry.

[62]  P. Pohl,et al.  The role of structural domains in RIP II toxin model membrane binding , 1997, FEBS letters.

[63]  Yongjun Chu,et al.  RNAi Factors are Present and Active in Human Cell Nuclei , 2014, Cell reports.

[64]  C. Croce,et al.  miRNAs, Cancer, and Stem Cell Division , 2005, Cell.

[65]  A. Bradley,et al.  Identification of mammalian microRNA host genes and transcription units. , 2004, Genome research.

[66]  H. Buermans,et al.  Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions , 2012, Nucleic acids research.

[67]  B. Cullen,et al.  Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. , 2003, Genes & development.

[68]  E. Kroh,et al.  Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma , 2011, Proceedings of the National Academy of Sciences.

[69]  Dieter Jocham,et al.  A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer. , 2010, Urologic oncology.

[70]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[71]  J. Tosar,et al.  Assessment of small RNA sorting into different extracellular fractions revealed by high-throughput sequencing of breast cell lines , 2015, Nucleic acids research.

[72]  Luigi Naldini,et al.  Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state , 2007, Nature Biotechnology.

[73]  N. Park,et al.  Salivary microRNA: Discovery, Characterization, and Clinical Utility for Oral Cancer Detection , 2009, Clinical Cancer Research.

[74]  P. Pohl,et al.  Membrane fusion mediated by ricin and viscumin. , 1998, Biochimica et biophysica acta.

[75]  M. Chopp,et al.  Functional microRNA is transferred between glioma cells. , 2010, Cancer research.

[76]  Jessica A. Weber,et al.  The microRNA spectrum in 12 body fluids. , 2010, Clinical chemistry.

[77]  Steven J. Greco,et al.  Gap junction-mediated import of microRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. , 2011, Cancer research.

[78]  Luca Sterpone,et al.  Microvesicles Derived from Adult Human Bone Marrow and Tissue Specific Mesenchymal Stem Cells Shuttle Selected Pattern of miRNAs , 2010, PloS one.

[79]  Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity , 2009 .

[80]  Aled Clayton,et al.  Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids , 2006, Current protocols in cell biology.

[81]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[82]  Daniel B. Martin,et al.  Circulating microRNAs as stable blood-based markers for cancer detection , 2008, Proceedings of the National Academy of Sciences.

[83]  Barbara Burwinkel,et al.  Extracellular miRNAs: the mystery of their origin and function. , 2012, Trends in biochemical sciences.

[84]  Grace X. Y. Zheng,et al.  MicroRNAs can generate thresholds in target gene expression , 2011, Nature Genetics.

[85]  Justine R. Smith,et al.  Sequence- and target-independent angiogenesis suppression by siRNA via TLR3 , 2008, Nature.

[86]  S. Akira,et al.  Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8 , 2004, Science.

[87]  B. Beutler,et al.  Intracellular toll-like receptors. , 2010, Immunity.

[88]  D. Davis,et al.  MicroRNAs Transfer from Human Macrophages to Hepato-Carcinoma Cells and Inhibit Proliferation , 2013, The Journal of Immunology.

[89]  M. Tewari,et al.  Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions , 2014, Nucleic acids research.

[90]  Marcela Dávila López,et al.  Small RNA deep sequencing discriminates subsets of extracellular vesicles released by melanoma cells – Evidence of unique microRNA cargos , 2015, RNA biology.

[91]  M. Rosen,et al.  Connexin‐specific cell‐to‐cell transfer of short interfering RNA by gap junctions , 2005, The Journal of physiology.

[92]  Mark A. Ragan,et al.  Quantitative Prediction of miRNA-mRNA Interaction Based on Equilibrium Concentrations , 2011, PLoS Comput. Biol..

[93]  V. Kim,et al.  Short structured RNAs with low GC content are selectively lost during extraction from a small number of cells. , 2012, Molecular cell.