RISCy Business: MicroRNAs, Pathogenesis, and Viruses
2007; Elsevier BV; Volume: 282; Issue: 37 Linguagem: Inglês
10.1074/jbc.r700023200
ISSN1083-351X
Autores Tópico(s)Plant and Fungal Interactions Research
ResumoProteins serve important regulatory and effector functions inside cells. However, the recent discovery that plants and animals have thousands of genes that encode non-protein-coding (nc)RNAs has opened a new vista on RNA-mediated biology. NcRNAs include rRNA, tRNA, small nuclear (sn)RNA, small nucleolar (sno)RNAs, micro-(mi)RNAs, and some of the lesser known RNAs such as vault RNAs, Y RNAs, repeat-associated small interfering (rasi)-RNAs, and PIWI-interacting (pi)RNAs (reviewed in Ref. 1Backofen R. Bernhart S.H. Flamm C. Fried C. Fritzsch G. Hackermuller J. Hertel J. Hofacker I.L. Missal K. Mosig A. Prohaska S.J. Rose D. Stadler P.F. Tanzer A. Washietl S. Will S. J. Exp. Zool. B Mol. Dev. Evol. 2007; 308: 1-25PubMed Google Scholar). Emerging data now suggest that whereas 2% of the human genome encodes for protein-coding RNAs, 60–70% of our DNA is transcribed into ncRNAs (2Mattick J.S. Makunin I.V. Hum. Mol. Genet. 2006; 15: R17-R29Crossref PubMed Scopus (0) Google Scholar, 3Washietl S. Hofacker I.L. Lukasser M. Huttenhofer A. Stadler P.F. Nat. Biotechnol. 2005; 23: 1383-1390Crossref PubMed Scopus (312) Google Scholar). Thus, the earlier view that ncRNAs are largely, if not exclusively, constituted by the relatively abundant rRNA, tRNA, snRNA, and snoRNA moieties is likely an oversimplification. More sensitive analytical methods such as reverse transcription-PCR and DNA tiling arrays have revealed that genomes of complex organisms are replete with numerous less abundant ncRNAs, which can contribute a hitherto unrecognized regulatory dimension. The first miRNA, 2The abbreviations used are:miRNAmicro-RNAncRNAnon-protein-coding RNApri-miRNAprimary miRNAvmiRNAviral miRNARISCRNA-induced silencing complexmi-RISCmiRNA-armed RISCsiRNAsmall interfering RNARNAiRNA interferenceHCVhepatitis C virusHIVhuman immunodeficiency virusmiwiRNAmurine Piwi RNA. lin-4, and its target mRNA, lin-14, were described in Caenorhabiditis elegans by Ambros, Ruvkun, and colleagues in 1993 (4Lee R.C. Feinbaum R.L. Ambros V. Cell. 1993; 75: 843-854Abstract Full Text PDF PubMed Scopus (8441) Google Scholar, 5Wightman B. Ha I. Ruvkun G. Cell. 1993; 75: 855-862Abstract Full Text PDF PubMed Scopus (2802) Google Scholar). Subsequently, computational analysis of aligned regions between human, mouse, and puffer fish genomes initially led to the prediction of ∼255 discrete miR-NAs in the Homo sapiens genome (6Lim L.P. Glasner M.E. Yekta S. Burge C.B. Bartel D.P. Science. 2003; 299: 1540Crossref PubMed Scopus (963) Google Scholar). That early number has been quickly exceeded by the latest enumeration of 474 characterized human miRNAs in the Sanger miRBase sequence data base (release 9.1). Later in silico estimates have posited ∼1000 or more human miRNAs (7Berezikov E. Guryev V. van de Belt J. Wienholds E. Plasterk R.H. Cuppen E. Cell. 2005; 120: 21-24Abstract Full Text Full Text PDF PubMed Scopus (964) Google Scholar, 8Bentwich I. Avniel A. Karov Y. Aharonov R. Gilad S. Barad O. Barzilai A. Einat P. Einav U. Meiri E. Sharon E. Spector Y. Bentwich Z. Nat. Genet. 2005; 37: 766-770Crossref PubMed Scopus (1480) Google Scholar); some of these newer suggestions have been verified by direct cloning and RAKE (RNA-primed, array-based Klenow enzyme) assay (9Berezikov E. van Tetering G. Verheul M. van de Belt J. van Laake L. Vos J. Verloop R. van de Wetering M. Guryev V. Takada S. van Zonneveld A.J. Mano H. Plasterk R. Cuppen E. Genome Res. 2006; 16: 1289-1298Crossref PubMed Scopus (212) Google Scholar). Currently, difficulties with the reliability of computer-based miRNA prediction can be attributed to the absence of any single property sufficient for accurate determination and the realization that novel miRNAs, by definition, may contain characteristics not fully recognized by extant pattern algorithms. Additionally, experimental confirmation (e.g. direct cloning) of miRNAs remains challenging because expression profiles of ncRNAs can be constrained temporally, spatially, and in a tissue-specific fashion. Moreover, the expression levels of individual miRNAs can vary by 3 orders of magnitude (10Neely L.A. Patel S. Garver J. Gallo M. Hackett M. McLaughlin S. Nadel M. Harris J. Gullans S. Rooke J. Nat. Methods. 2006; 3: 41-46Crossref PubMed Scopus (232) Google Scholar). Indeed, in a recent extensive miRNA cloning attempt to identify novel miRNAs, the investigators reported that 76% of their new miRNAs were cloned only once and that they failed to clone ∼100 discrete human miRNAs that had been documented previously by others (9Berezikov E. van Tetering G. Verheul M. van de Belt J. van Laake L. Vos J. Verloop R. van de Wetering M. Guryev V. Takada S. van Zonneveld A.J. Mano H. Plasterk R. Cuppen E. Genome Res. 2006; 16: 1289-1298Crossref PubMed Scopus (212) Google Scholar). This experience illustrates the rigor and challenges encountered in attempts to validate rare miRNAs that are expressed at low levels. micro-RNA non-protein-coding RNA primary miRNA viral miRNA RNA-induced silencing complex miRNA-armed RISC small interfering RNA RNA interference hepatitis C virus human immunodeficiency virus murine Piwi RNA. Human miRNAs are present in introns of coding genes and introns and exons of noncoding transcripts (11Rodriguez A. Griffiths-Jones S. Ashurst J.L. Bradley A. Genome Res. 2004; 14: 1902-1910Crossref PubMed Scopus (1419) Google Scholar). MiRNAs are small ncRNAs of 18–25 nucleotides. A mature miRNA begins with the transcription by RNA polymerase II of a long primary transcript (pri-miRNAs) that contains a "hairpin" structure. pri-miRNA is first cropped in the nucleus into an ∼70-nucleotide stem-loop RNA intermediate (pre-miRNA) by a protein complex that contains the Drosha ribonuclease with an RNA-binding protein, known as DGCR8 in humans (12Han J. Lee Y. Yeom K.H. Kim Y.K. Jin H. Kim V.N. Genes Dev. 2004; 18: 3016-3027Crossref PubMed Scopus (1377) Google Scholar). The pre-miRNA is then ferried by Exportin 5 into the cytoplasm (13Bohnsack M.T. Czaplinski K. Gorlich D. RNA (Cold Spring Harbor). 2004; 10: 185-191Google Scholar) and further processed by a cytoplasmic ribonuclease III enzyme, Dicer, to mature miRNA (Fig. 1A). One strand of this mature double-stranded miRNA is destined as the guide strand, with the other as the passenger strand. The guide strand is channeled by Dicer-interacting proteins PACT and TAR RNA-binding protein (TRBP) (14Lee Y. Hur I. Park S.Y. Kim Y.K. Suh M.R. Kim V.N. EMBO J. 2006; 25: 522-532Crossref PubMed Scopus (476) Google Scholar, 15Chendrimada T.P. Gregory R.I. Kumaraswamy E. Norman J. Cooch N. Nishikura K. Shiekhattar R. Nature. 2005; 436: 740-744Crossref PubMed Scopus (1463) Google Scholar, 16Gatignol A. Buckler-White A. Berkhout B. Jeang K.T. Science. 1991; 251: 1597-1600Crossref PubMed Google Scholar) into an RNA-induced silencing complex (RISC). A detailed review of miRNA biogenesis and RISC complex formation has been presented elsewhere (17Kim V.N. Nat. Rev. Mol. Cell Biol. 2005; 6: 376-385Crossref PubMed Scopus (1826) Google Scholar). An miRNA-armed RISC (mi-RISC) mediates miRNA function(s) inside cells. In plants, mi-RISC use miRNA guides that are perfectly complementary to either the coding region or the 3′-untranslated region of cognate mRNAs. In the setting of an miRNA-mRNA interaction driven by perfect complementarity, plant mi-RISC can mediate mRNA cleavage/degradation similar to that described for siRNA (or si-RISC)-mediated silencing (18Fire A. Xu S. Montgomery M.K. Kostas S.A. Driver S.E. Mello C.C. Nature. 1998; 391: 806-811Crossref PubMed Scopus (10727) Google Scholar, 19Elbashir S.M. Harborth J. Lendeckel W. Yalcin A. Weber K. Tuschl T. Nature. 2001; 411: 494-498Crossref PubMed Scopus (7747) Google Scholar). By contrast, animal and human mi-RISC recognize target mRNAs using base-pairing in a manner tolerant of mismatches. Thus, in animal cells, the imperfect miRNA-mRNA complementarity is commonly composed of matched nucleotides at positions 2–7 (termed the seed sequence) in the 5′-portion of the miRNA (20Lewis B.P. Burge C.B. Bartel D.P. Cell. 2005; 120: 15-20Abstract Full Text Full Text PDF PubMed Scopus (9082) Google Scholar) (Fig. 1B) with mismatched nucleotides at positions 10 and 11. These mismatches preclude the endonucleolytic cleavage of mRNA, a phenomenon normally observed with si-RISC-mediated RNA interference (RNAi), by mi-RISC. Once a mi-RISC-mRNA interaction forms in a human cell, how does the resulting complex trigger mRNA silencing? As yet, the answer to this question remains incompletely elucidated and somewhat controversial. Nonetheless, current data are compatible with multiple miRNA mechanisms that either repress mRNA translation or enforce premature mRNA decay. There is evidence that mi-RISC-mRNA interaction can promote inhibition of translational initiation, increase co-translational degradation of nascent proteins, reduce the elongation rate of translation, and/or increase the rate of mRNA deadenylation (21Humphreys D.T. Westman B.J. Martin D.I. Preiss T. Proc. Natl. Acad. Sci. U. S. 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Shiekhattar R. Nature. 2007; 447: 823-828Crossref PubMed Scopus (358) Google Scholar). Which mechanism operates under what conditions remains contested. However, the retention of mi-RISC-mRNA in ribosome-free translationally silent cytoplasmic organelles termed processing bodies (P-bodies) does appear to account for some aspects of silencing (28Liu J. Rivas F.V. Wohlschlegel J. Yates J.R. II I Parker R. Hannon G.J. Nat. Cell Biol. 2005; 7: 1261-1266Crossref PubMed Scopus (476) Google Scholar, 29Sen G.L. Blau H.M. Nat. Cell Biol. 2005; 7: 633-636Crossref PubMed Scopus (470) Google Scholar). What roles are served by the several hundred characterized human miRNAs? Currently, only a handful of human mRNAs have been validated as specific targets for miRNAs. Extant bioinformatic predictions suggest that a single miRNA through imperfect complementarity can potentially target ∼100 different mRNAs (30Brennecke J. Stark A. Russell R.B. Cohen S.M. PLoS. Biol. 2005; 3: e85Crossref PubMed Scopus (1713) Google Scholar). A reasonable extrapolation from these predictions argues that up to 30% of all mammalian genes are under some degree of miRNA regulation (31John B. Enright A.J. Aravin A. Tuschl T. Sander C. Marks D.S. PLoS. Biol. 2004; 2: e363Crossref PubMed Scopus (2638) Google Scholar). Experimental observations do support important physiological roles contributed by miRNAs. For instance, in C. elegans, zebrafish, Drosophila, mice, and humans, miRNA expression occurs with tissue-restricted profiles (32Lagos-Quintana M. Rauhut R. Yalcin A. Meyer J. Lendeckel W. Tuschl T. Curr. Biol. 2002; 12: 735-739Abstract Full Text Full Text PDF PubMed Scopus (2537) Google Scholar, 33Sempere L.F. Freemantle S. Pitha-Rowe I. Moss E. Dmitrovsky E. Ambros V. Genome Biol. 2004; 5: R13Crossref PubMed Google Scholar, 34Barad O. Meiri E. Avniel A. Aharonov R. Barzilai A. Bentwich I. Einav U. Gilad S. Hurban P. Karov Y. Lobenhofer E.K. Sharon E. 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Both patterns suggest that miRNAs contribute to morphological development and organogenesis. Studies that have depleted Dicer, the RNase III enzyme critical to miRNA maturation, from zebrafish and mice have been functionally informative. Knock-out of Dicer in zebrafish arrests embryo development 8 days after fertilization (40Wienholds E. Koudijs M.J. van Eeden F.J. Cuppen E. Plasterk R.H. Nat. Genet. 2003; 35: 217-218Crossref PubMed Scopus (349) Google Scholar), and dicer-deficient mice lose viability prior to axis formation during gastrulation (41Bernstein E. Kim S.Y. Carmell M.A. Murchison E.P. Alcorn H. Li M.Z. Mills A.A. Elledge S.J. Anderson K.V. Hannon G.J. Nat. Genet. 2003; 35: 215-217Crossref PubMed Scopus (1457) Google Scholar). Conditional depletion of Dicer in mice has shown that general loss of miRNA function(s) affects T-cell development (42Cobb B.S. Nesterova T.B. Thompson E. Hertweck A. O'Connor E. Godwin J. Wilson C.B. Brockdorff N. Fisher A.G. Smale S.T. 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Some of these results should be interpreted cautiously because Dicer is known to play roles in heterochromatin formation and chromosome segregation in yeast Schizosaccharomyces pombe, which apparently does not encode any known miRNAs. Hence, Dicer has functions beyond miRNA processing, and some of the multicellular loss-of-Dicer phenotypes could occur independently of miRNA effects. The notion that miRNAs are involved in human diseases arises from two sets of observations. A clue that dysfunction of miRNA-pathway(s) contributes to pathology came from the recognition that humans with mutations in DGCR8 (a Drosha cofactor) or fragile X (a RISC cofactor) suffer, respectively, from DiGeorge syndrome (47Landthaler M. Yalcin A. Tuschl T. Curr. Biol. 2004; 14: 2162-2167Abstract Full Text Full Text PDF PubMed Scopus (609) Google Scholar) and mental retardation (48Jin P. Zarnescu D.C. Ceman S. Nakamoto M. Mowrey J. Jongens T.A. Nelson D.L. Moses K. Warren S.T. Nat. Neurosci. 2004; 7: 113-117Crossref PubMed Scopus (495) Google Scholar, 49Jin P. Alisch R.S. Warren S.T. Nat. Cell Biol. 2004; 6: 1048-1053Crossref PubMed Scopus (272) Google Scholar). Second, >50% of human miRNA genes are present at genetic loci (such as fragile sites, common break point regions, etc.) implicated in cancers. Accordingly, miRNA expression patterns are invariably found to be very different in tumor tissues when compared with matched normals. Indeed, in studies of 334 leukemia and 540 primary tumors, Lu et al. (50Lu J. Getz G. Miska E.A. varez-Saavedra E. Lamb J. Peck D. Sweet-Cordero A. Ebert B.L. Mak R.H. Ferrando A.A. Downing J.R. Jacks T. Horvitz H.R. Golub T.R. Nature. 2005; 435: 834-838Crossref PubMed Scopus (7575) Google Scholar) and Volinia et al. (51Volinia S. Calin G.A. Liu C.G. Ambs S. Cimmino A. Petrocca F. Visone R. Iorio M. Roldo C. Ferracin M. Prueitt R.L. Yanaihara N. Lanza G. Scarpa A. Vecchione A. Negrini M. Harris C.C. Croce C.M. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 2257-2261Crossref PubMed Scopus (4615) Google Scholar), respectively, observed miRNA cancer signatures that distinguished tumors based on their tissue origin. Other miRNA profiling studies have also substantiated malignancy-specific expression patterns in lung (52Yanaihara N. Caplen N. Bowman E. Seike M. Kumamoto K. Yi M. Stephens R.M. Okamoto A. Yokota J. Tanaka T. Calin G.A. Liu C.G. Croce C.M. Harris C.C. Cancer Cell. 2006; 9: 189-198Abstract Full Text Full Text PDF PubMed Scopus (2546) Google Scholar), colon (53Cummins J.M. Velculescu V.E. Oncogene. 2006; 25: 6220-6227Crossref PubMed Scopus (209) Google Scholar), breast (54Iorio M.V. Ferracin M. Liu C.G. Veronese A. Spizzo R. Sabbioni S. Magri E. Pedriali M. Fabbri M. Campiglio M. Menard S. Palazzo J.P. Rosenberg A. Musiani P. Volinia S. Nenci I. Calin G.A. Querzoli P. Negrini M. Croce C.M. Cancer Res. 2005; 65: 7065-7070Crossref PubMed Scopus (3247) Google Scholar), and heptacellular (55Murakami Y. Yasuda T. Saigo K. Urashima T. Toyoda H. Okanoue T. Shimotohno K. Oncogene. 2006; 25: 2537-2545Crossref PubMed Scopus (974) Google Scholar) cancers. A recent study has added indirect support that miRNA changes are causal, rather than consequential, of cellular transformation (56Kumar M.S. Lu J. Mercer K.L. Golub T.R. Jacks T. Nat. Genet. 2007; 39: 673-677Crossref PubMed Scopus (1173) Google Scholar). How then do miRNA changes promote human carcinogenesis? The full answer is unknown, but there are several ways that one could consider mechanisms. One perspective posits that some miRNAs are tumor suppressors, whereas other miRNAs are oncogenes (see Table 1). Reduced expression of the former or gained expression of the latter would confer a growth advantage to cells. Experimental data support that miR-15a and miR-16-1 provide tumor suppressor function by targeting Bcl2 (57Cimmino A. Calin G.A. Fabbri M. Iorio M.V. Ferracin M. Shimizu M. Wojcik S.E. Aqeilan R.I. Zupo S. Dono M. Rassenti L. Alder H. Volinia S. Liu C.G. Kipps T.J. Negrini M. Croce C.M. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 13944-13949Crossref PubMed Scopus (2785) Google Scholar), and miR-155 is oncogenic through incompletely understood effects on perhaps PU.1 and C/EBPβ (58Eis P.S. Tam W. Sun L. Chadburn A. Li Z. Gomez M.F. Lund E. Dahlberg J.E. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 3627-3632Crossref PubMed Scopus (1137) Google Scholar). However, one must entertain the possibility of tissue-specific determinants of miRNA function when interpreting findings. Thus, although miR-15a and miR-16-1 are down-regulated in chronic lymphocytic leukemia (consistent with their postulated tumor suppressor function (59Calin G.A. Ferracin M. Cimmino A. Di L.G. Shimizu M. Wojcik S.E. Iorio M.V. Visone R. Sever N.I. Fabbri M. Iuliano R. Palumbo T. Pichiorri F. Roldo C. Garzon R. Sevignani C. Rassenti L. Alder H. Volinia S. Liu C.G. Kipps T.J. Negrini M. Croce C.M. N. Engl. J. Med. 2005; 353: 1793-1801Crossref PubMed Scopus (1967) Google Scholar)), the same miRNAs are paradoxically overexpressed in endocrine pancreatic tumors (60Roldo C. Missiaglia E. Hagan J.P. Falconi M. Capelli P. Bersani S. Calin G.A. Volinia S. Liu C.G. Scarpa A. Croce C.M. J. Clin. Oncol. 2006; 24: 4677-4684Crossref PubMed Scopus (627) Google Scholar).TABLE 1Selected examples of human miRNAs and their proposed functional targetsmiRNATargetsReference no.Tumor suppressorslet 7Ras, Hmga298Johnson S.M. Grosshans H. Shingara J. Byrom M. Jarvis R. Cheng A. Labourier E. Reinert K.L. Brown D. Slack F.J. Cell. 2005; 120: 635-647Abstract Full Text Full Text PDF PubMed Scopus (2938) Google ScholarmiR-15aBcl257Cimmino A. Calin G.A. Fabbri M. Iorio M.V. Ferracin M. Shimizu M. Wojcik S.E. Aqeilan R.I. Zupo S. Dono M. Rassenti L. Alder H. Volinia S. Liu C.G. Kipps T.J. Negrini M. Croce C.M. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 13944-13949Crossref PubMed Scopus (2785) Google ScholarmiR-16-1Bcl257Cimmino A. Calin G.A. Fabbri M. Iorio M.V. Ferracin M. Shimizu M. Wojcik S.E. Aqeilan R.I. Zupo S. Dono M. Rassenti L. Alder H. Volinia S. Liu C.G. Kipps T.J. Negrini M. Croce C.M. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 13944-13949Crossref PubMed Scopus (2785) Google ScholarmiR-127Bcl699Saito Y. Liang G. Egger G. Friedman J.M. Chuang J.C. Coetzee G.A. Jones P.A. Cancer Cell. 2006; 9: 435-443Abstract Full Text Full Text PDF PubMed Scopus (1109) Google ScholarTumor inducersmiR-155PU.1, C/EBPβ58Eis P.S. Tam W. Sun L. Chadburn A. Li Z. Gomez M.F. Lund E. Dahlberg J.E. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 3627-3632Crossref PubMed Scopus (1137) Google ScholarmiR-17-92E2F1100O'Donnell K.A. Wentzel E.A. Zeller K.I. Dang C.V. Mendell J.T. Nature. 2005; 435: 839-843Crossref PubMed Scopus (2343) Google ScholarmiR-106aR6151Volinia S. Calin G.A. Liu C.G. Ambs S. Cimmino A. Petrocca F. Visone R. Iorio M. Roldo C. Ferracin M. Prueitt R.L. Yanaihara N. Lanza G. Scarpa A. Vecchione A. Negrini M. Harris C.C. Croce C.M. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 2257-2261Crossref PubMed Scopus (4615) Google ScholarmiR-21Tpmi101Zhu S. Si M.L. Wu H. Mo Y.Y. J. Biol. Chem. 2007; 282: 14328-14336Abstract Full Text Full Text PDF PubMed Scopus (885) Google ScholarInflammationmiR-146IRAK1, TRAF6102Taganov K.D. Boldin M.P. Chang K.J. Baltimore D. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 12481-12486Crossref PubMed Scopus (3103) Google ScholarmiR-155?87O'Connell R.M. Taganov K.D. Boldin M.P. Cheng G. Baltimore D. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 1604-1609Crossref PubMed Scopus (1422) Google Scholarlet 7aNF288Meng F. Henson R. Wehbe-Janek H. Smith H. Ueno Y. Patel T. J. Biol. Chem. 2007; 282: 8256-8264Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Open table in a new tab MiRNA changes in cancers offer suggestive correlations, which are insufficient to prove conclusively their causality for carcinogenesis. Direct validation of causality can, however, emerge from studying transforming viruses that do not encode oncogenes but do integrate near genome loci whose expression drives tumorigenesis. Using such an approach, the first proof of an oncogenic miRNA causal of cancer, was miR-155/BIC (reviewed in Ref. 61Tam W. Dahlberg J.E. Genes Chromosomes Cancer. 2006; 45: 211-212Crossref PubMed Scopus (96) Google Scholar), which was activated in chicken tumors by retroviral insertion (i.e. avian leukosis virus integration). Overexpression of human miR-155/BIC has subsequently been linked to the development of Hodgkin's (58Eis P.S. Tam W. Sun L. Chadburn A. Li Z. Gomez M.F. Lund E. Dahlberg J.E. Proc. Natl. Acad. Sci. U. S. 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Tuschl T. Nat. Meth. 2005; 2: 269-276Crossref PubMed Scopus (790) Google Scholar) have failed to predict and clone small viral ncRNAs described by others (91Bennasser Y. Le S.Y. Benkirane M. Jeang K.T. Immunity. 2005; 22: 607-619Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 92Omoto S. Ito M. Tsutsumi Y. Ichikawa Y. Okuyama H. Brisibe E.A. Saksena N.K. Fujii Y.R. Retrovirology. 2004; 1: 44Crossref PubMed Scopus (207) Google Scholar). Nonetheless, this type of failing should be interpreted with circumspection. For instance, three separate studies on vmiRNAs encoded by herpes simplex virus type 1 (HSV-1) illustrate the potential for discrepant results. Two of the three studies (93Cui C. Griffiths A. Li G. Silva L.M. Kramer M.F. Gaasterland T. Wang X.J. Coen D.M. J. Virol. 2006; 80: 5499-5508Crossref PubMed Scopus (170) Google Scholar, 94Gupta A. Gartner J.J. Sethupathy P. Hatzigeorgiou A.G. Fraser N.W. 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Viruses may mutate to escape restriction and even evolve adaptations (e.g. the emergence of T20 (an anti-viral peptide)-dependent HIV-1 replication after initial negative selection against HIV-1 by T20 (96Baldwin C.E. Sanders R.W. Deng Y. Jurriaans S. Lange J.M. Lu M. Berkhout B. J. Virol. 2004; 78: 12428-12437Crossref PubMed Scopus (128) Google Scholar)) to turn negative effects into positive factors (Fig. 2). This type of virus-host, cat-and-mouse interplay may ultimately limit the antiviral effectiveness of RNAi and could explain how, unlike other viruses, HCV co-opts a cellular miRNA for enhancing, rather than inhibiting, viral replication (79Jopling C.L. Yi M. Lancaster A.M. Lemon S.M. Sarnow P. Science. 2005; 309: 1577-1581Crossref PubMed Scopus (1970) Google Scholar) (Fig. 2). The past few years have been exciting and challenging for studying ncRNAs. It is a safe prediction that many new rules, principles, and functions of small RNAs await elucidation. On the horizon are nascent findings that small RNAs may also serve gene activating rather than gene silencing functions (97Rossi J.J. Nat. Chem. Biol. 2007; 3: 136-137Crossref PubMed Scopus (12) Google Scholar). New discoveries in the coming days will likely further advance our knowledge of miRNAs and their applications toward human diseases. We thank P. Yeung, A. Pearl-Jacobvitz, and A. Dayton for assistance with the manuscript.
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