Key Points
-
MicroRNAs (miRNAs) have important roles in many aspects of human diseases, and their targeted inhibition may have substantial therapeutic impact.
-
Inhibition of miRNAs can be achieved through a variety of methods and chemically modified antisense oligonucleotides (anti-miRs) have shown the most prominent effects.
-
Targeted delivery of anti-miRs is crucial to achieve intended therapeutic effects, and further efforts are warranted to develop more efficient delivery systems.
Abstract
MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that have crucial roles in regulating gene expression. Increasing evidence supports a role for miRNAs in many human diseases, including cancer and autoimmune disorders. The function of miRNAs can be efficiently and specifically inhibited by chemically modified antisense oligonucleotides, supporting their potential as targets for the development of novel therapies for several diseases. In this Review we summarize our current knowledge of the design and performance of chemically modified miRNA-targeting antisense oligonucleotides, discuss various in vivo delivery strategies and analyse ongoing challenges to ensure the specificity and efficacy of therapeutic oligonucleotides in vivo. Finally, we review current progress on the clinical development of miRNA-targeting therapeutics.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
£139.00 per year
only £11.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).
Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).
Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).
Klattenhoff, C. & Theurkauf, W. Biogenesis and germline functions of piRNAs. Development 135, 3–9 (2008).
Ghildiyal, M. et al. Endogenous siRNAs derived from transposons and mRNAs in Drosophila somatic cells. Science 320, 1077–1081 (2008).
Calin, G. A. et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc. Natl Acad. Sci. USA 101, 11755–11760 (2004).
Calin, G. A. et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl Acad. Sci. USA 101, 2999–3004 (2004).
Farazi, T. A., Spitzer, J. I., Morozov, P. & Tuschl, T. miRNAs in human cancer. J. Pathol. 223, 102–115 (2011).
van Rooij, E. & Olson, E. N. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nature Rev. Drug Discov. 11, 860–872 (2012).
O'Connell, R. M., Rao, D. S., Chaudhuri, A. A. & Baltimore, D. Physiological and pathological roles for microRNAs in the immune system. Nature Rev. Immunol. 10, 111–122 (2010).
Esau, C. C. Inhibition of microRNA with antisense oligonucleotides. Methods 44, 55–60 (2008).
Lennox, K. A. & Behlke, M. A. Chemical modification and design of anti-miRNA oligonucleotides. Gene Ther. 18, 1111–1120 (2011).
Bumcrot, D., Manoharan, M., Koteliansky, V. & Sah, D. W. RNAi therapeutics: a potential new class of pharmaceutical drugs. Nature Chem. Biol. 2, 711–719 (2006).
Lanford, R. E. et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327, 198–201 (2010).
Krutzfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438, 685–689 (2005).
Elmen, J. et al. LNA-mediated microRNA silencing in non-human primates. Nature 452, 896–899 (2008).
Li, Z. & Rana, T. M. Molecular mechanisms of RNA-triggered gene silencing machineries. Accounts Chem. Res. 45, 1122–1131 (2012).
Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nature Rev. Genet. 11, 597–610 (2010).
Han, J. et al. Posttranscriptional crossregulation between Drosha and DGCR8. Cell 136, 75–84 (2009).
Triboulet, R., Chang, H. M., Lapierre, R. J. & Gregory, R. I. Post-transcriptional control of DGCR8 expression by the microprocessor. RNA 15, 1005–1011 (2009).
Gregory, R. I. et al. The microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).
Chendrimada, T. P. et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436, 740–744 (2005).
Melo, S. A. et al. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. Nature Genet. 41, 365–370 (2009).
Paroo, Z., Ye, X., Chen, S. & Liu, Q. Phosphorylation of the human microRNA-generating complex mediates MAPK/Erk signaling. Cell 139, 112–122 (2009).
Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).
Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).
Wightman, B., Ha, I. & Ruvkun, G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855–862 (1993).
Pillai, R. S. et al. Inhibition of translational initiation by Let-7 microRNA in human cells. Science 309, 1573–1576 (2005).
Olsen, P. H. & Ambros, V. The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev. Biol. 216, 671–680 (1999).
Petersen, C. P., Bordeleau, M. E., Pelletier, J. & Sharp, P. A. Short RNAs repress translation after initiation in mammalian cells. Mol. Cell 21, 533–542 (2006).
Lytle, J. R., Yario, T. A. & Steitz, J. A. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc. Natl Acad. Sci. USA 104, 9667–9672 (2007).
Bagga, S. et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122, 553–563 (2005).
Guo, H., Ingolia, N. T., Weissman, J. S. & Bartel, D. P. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835–840 (2010).
Liu, J. et al. A role for the P-body component GW182 in microRNA function. Nature Cell Biol. 7, 1261–1266 (2005).
Eulalio, A., Huntzinger, E. & Izaurralde, E. GW182 interaction with Argonaute is essential for miRNA-mediated translational repression and mRNA decay. Nature Struct. Mol. Biol. 15, 346–353 (2008).
Behm-Ansmant, I. et al. mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev. 20, 1885–1898 (2006).
Chu, C. Y. & Rana, T. M. Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS Biol. 4, e210 (2006).
Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).
Stark, A., Brennecke, J., Russell, R. B. & Cohen, S. M. Identification of Drosophila microRNA targets. PLoS Biol. 1, E60 (2003).
Grun, D., Wang, Y. L., Langenberger, D., Gunsalus, K. C. & Rajewsky, N. microRNA target predictions across seven Drosophila species and comparison to mammalian targets. PLoS Comput. Biol. 1, e13 (2005).
Gaidatzis, D., van Nimwegen, E., Hausser, J. & Zavolan, M. Inference of miRNA targets using evolutionary conservation and pathway analysis. BMC Bioinformatics 8, 69 (2007).
Ma, L. et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nature Cell Biol. 12, 247–256 (2010).
Li, Z., Yang, C. S., Nakashima, K. & Rana, T. M. Small RNA-mediated regulation of iPS cell generation. EMBO J. 30, 823–834 (2011).
Papagiannakopoulos, T., Shapiro, A. & Kosik, K. S. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 68, 8164–8172 (2008).
Johnson, C. D. et al. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res. 67, 7713–7722 (2007).
Ebert, M. S., Neilson, J. R. & Sharp, P. A. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nature Methods 4, 721–726 (2007).
Ebert, M. S. & Sharp, P. A. MicroRNA sponges: progress and possibilities. RNA 16, 2043–2050 (2010).
Tay, Y. et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147, 344–357 (2011).
Cesana, M. et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).
Karreth, F. A. et al. In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 147, 382–395 (2011).
Gumireddy, K. et al. Small-molecule inhibitors of microRNA miR-21 function. Angew. Chem. Int. Ed. Engl. 47, 7482–7484 (2008).
Young, D. D., Connelly, C. M., Grohmann, C. & Deiters, A. Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma. J. Am. Chem. Soc. 132, 7976–7981 (2010).
Boutla, A., Delidakis, C. & Tabler, M. Developmental defects by antisense-mediated inactivation of micro-RNAs 2 and 13 in Drosophila and the identification of putative target genes. Nucleic Acids Res. 31, 4973–4980 (2003).
Lamond, A. I. & Sproat, B. S. Antisense oligonucleotides made of 2′-O-alkylRNA: their properties and applications in RNA biochemistry. FEBS Lett. 325, 123–127 (1993).
Verma, S. & Eckstein, F. Modified oligonucleotides: synthesis and strategy for users. Annu. Rev. Biochem. 67, 99–134 (1998).
Cummins, L. L. et al. Characterization of fully 2′-modified oligoribonucleotide hetero- and homoduplex hybridization and nuclease sensitivity. Nucleic Acids Res. 23, 2019–2024 (1995).
Majlessi, M., Nelson, N. C. & Becker, M. M. Advantages of 2′-O-methyl oligoribonucleotide probes for detecting RNA targets. Nucleic Acids Res. 26, 2224–2229 (1998).
Hutvagner, G., Simard, M. J., Mello, C. C. & Zamore, P. D. Sequence-specific inhibition of small RNA function. PLoS Biol. 2, E98 (2004).
Meister, G., Landthaler, M., Dorsett, Y. & Tuschl, T. Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 10, 544–550 (2004).
Lennox, K. A. & Behlke, M. A. A direct comparison of anti-microRNA oligonucleotide potency. Pharm. Res. 27, 1788–1799 (2010).
Geary, R. S. Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin. Drug Metab. Toxicol. 5, 381–391 (2009).
Chiu, Y. L. & Rana, T. M. RNAi in human cells: basic structural and functional features of small interfering RNA. Mol. Cell 10, 549–561 (2002).
Chiu, Y. L. & Rana, T. M. siRNA function in RNAi: a chemical modification analysis. RNA 9, 1034–1048 (2003).
Soutschek, J. et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432, 173–178 (2004).
Yu, D. et al. Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell 150, 895–908 (2012).
Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).
Ma, L. et al. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nature Biotech. 28, 341–347 (2010).
Manoharan, M. 2′-carbohydrate modifications in antisense oligonucleotide therapy: importance of conformation, configuration and conjugation. Biochim. Biophys. Acta 1489, 117–130 (1999).
Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell. Metab. 3, 87–98 (2006).
Kawasaki, A. M. et al. Uniformly modified 2′-deoxy-2′-fluoro phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets. J. Med. Chem. 36, 831–841 (1993).
Davis, S., Lollo, B., Freier, S. & Esau, C. Improved targeting of miRNA with antisense oligonucleotides. Nucleic Acids Res. 34, 2294–2304 (2006).
Rigo, F. et al. Synthetic oligonucleotides recruit ILF2/3 to RNA transcripts to modulate splicing. Nature Chem. Biol. 8, 555–561 (2012).
Petersen, M., Bondensgaard, K., Wengel, J. & Jacobsen, J. P. Locked nucleic acid (LNA) recognition of RNA: NMR solution structures of LNA:RNA hybrids. J. Am. Chem. Soc. 124, 5974–5982 (2002).
Singh, K. S., Koshkin, A. A., Wengel, J. & Nielsen, P. LNA (locked nucleic acids): synthesis and high-affinity nucleic acid recognition. Chem. Comm. 1998, 455–456 (1998).
Chan, J. A., Krichevsky, A. M. & Kosik, K. S. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65, 6029–6033 (2005).
Orom, U. A., Kauppinen, S. & Lund, A. H. LNA-modified oligonucleotides mediate specific inhibition of microRNA function. Gene 372, 137–141 (2006).
Koshkin, A. A. et al. LNA (locked nucleic acid): an RNA mimic forming exceedingly stable LNA:LNA duplexes. J. Am. Chem. Soc. 120, 13252–13253 (1998).
Elmen, J. et al. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res. 36, 1153–1162 (2008).
Obad, S. et al. Silencing of microRNA families by seed-targeting tiny LNAs. Nature Genet. 43, 371–378 (2011).
Lennox, K. A., Owczarzy, R., Thomas, D. M., Walder, J. A. & Behlke, M. A. Improved performance of anti-miRNA oligonucleotides using a novel non-nucleotide modifier. Mol. Ther. Nucleic Acids 2, e117 (2013).
Wolfrum, C. et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nature Biotech. 25, 1149–1157 (2007).
Nishina, K. et al. Efficient in vivo delivery of siRNA to the liver by conjugation of alpha-tocopherol. Mol. Ther. 16, 734–740 (2008).
Kortylewski, M. et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nature Biotech. 27, 925–932 (2009).
Hsu, T. & Mitragotri, S. Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. Proc. Natl Acad. Sci. USA 108, 15816–15821 (2011).
Morrissey, D. V. et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nature Biotech. 23, 1002–1007 (2005).
Morrissey, D. V. et al. Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication. Hepatology 41, 1349–1356 (2005).
Zimmermann, T. S. et al. RNAi-mediated gene silencing in non-human primates. Nature 441, 111–114 (2006).
Akinc, A. et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nature Biotech. 26, 561–569 (2008).
Akinc, A. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010).
Peer, D., Park, E. J., Morishita, Y., Carman, C. V. & Shimaoka, M. Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science 319, 627–630 (2008).
Palliser, D. et al. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature 439, 89–94 (2006).
Kumar, P., Lee, S. K., Shankar, P. & Manjunath, N. A single siRNA suppresses fatal encephalitis induced by two different flaviviruses. PLoS Med. 3, e96 (2006).
Malam, Y., Loizidou, M. & Seifalian, A. M. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol. Sci. 30, 592–599 (2009).
Davis, M. E., Chen, Z. G. & Shin, D. M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Rev. Drug Discov. 7, 771–782 (2008).
Schiffelers, R. M. et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 32, e149 (2004).
Heidel, J. D. et al. Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA. Proc. Natl Acad. Sci. USA 104, 5715–5721 (2007).
Hu-Lieskovan, S., Heidel, J. D., Bartlett, D. W., Davis, M. E. & Triche, T. J. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. Cancer Res. 65, 8984–8992 (2005).
Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010).
Baigude, H., McCarroll, J., Yang, C. S., Swain, P. M. & Rana, T. M. Design and creation of new nanomaterials for therapeutic RNAi. ACS Chem. Biol. 2, 237–241 (2007).
Su, J., Baigude, H., McCarroll, J. & Rana, T. M. Silencing microRNA by interfering nanoparticles in mice. Nucleic Acids Res. 39, e38 (2011).
Lee, H. et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nature Nanotech. 7, 389–393 (2012).
Song, E. et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nature Biotech. 23, 709–717 (2005).
Kumar, P. et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell 134, 577–586 (2008).
Wen, W. H. et al. Targeted inhibition of HBV gene expression by single-chain antibody mediated small interfering RNA delivery. Hepatology 46, 84–94 (2007).
Yao, Y. D. et al. Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis. Sci. Transl. Med. 4, 130ra148 (2012).
Lal, A. et al. miR-24 inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to “seedless” 3′UTR microRNA recognition elements. Mol. Cell 35, 610–625 (2009).
Kloosterman, W. P., Lagendijk, A. K., Ketting, R. F., Moulton, J. D. & Plasterk, R. H. Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development. PLoS Biol. 5, e203 (2007).
van Deutekom, J. C. et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N. Engl. J. Med. 357, 2677–2686 (2007).
Hammond, S. M. & Wood, M. J. PRO-051, an antisense oligonucleotide for the potential treatment of Duchenne muscular dystrophy. Curr. Opin. Mol. Ther. 12, 478–486 (2010).
Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunol. 11, 373–384 (2010).
Kariko, K., Bhuyan, P., Capodici, J. & Weissman, D. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J. Immunol. 172, 6545–6549 (2004).
Kleinman, M. E. et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452, 591–597 (2008).
Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).
Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).
Judge, A. D. et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nature Biotech. 23, 457–462 (2005).
Hornung, V. et al. Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nature Med. 11, 263–270 (2005).
Jurk, M. et al. Immunostimulatory potential of silencing RNAs can be mediated by a non-uridine-rich Toll-like receptor 7 motif. Nucleic Acid. Ther. 21, 201–214 (2011).
Bennett, C. F. & Swayze, E. E. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol. 50, 259–293 (2010).
Henry, S. P., Novotny, W., Leeds, J., Auletta, C. & Kornbrust, D. J. Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense Nucleic Acid Drug Dev. 7, 503–510 (1997).
Galbraith, W. M., Hobson, W. C., Giclas, P. C., Schechter, P. J. & Agrawal, S. Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. Antisense Res. Dev. 4, 201–206 (1994).
Hildebrandt-Eriksen, E. S. et al. A locked nucleic acid oligonucleotide targeting microRNA 122 is well-tolerated in cynomolgus monkeys. Nucleic Acid Ther. 22, 152–161 (2012).
Swayze, E. E. et al. Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals. Nucleic Acids Res. 35, 687–700 (2007).
Stanton, R. et al. Chemical modification study of antisense gapmers. Nucleic Acid. Ther. 22, 344–359 (2012).
Kakiuchi-Kiyota, S. et al. Comparison of hepatic transcription profiles of locked ribonucleic acid (LNA) antisense oligonucleotides: evidence of distinct pathways contributing to non-target mediated toxicity in mice. Toxicol. Sci. 138, 234–248 (2013).
Garzon, R., Marcucci, G. & Croce, C. M. Targeting microRNAs in cancer: rationale, strategies and challenges. Nature Rev. Drug Discov. 9, 775–789 (2010).
Matsubara, H. et al. Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92. Oncogene 26, 6099–6105 (2007).
Ventura, A. et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 132, 875–886 (2008).
Kang, S. G. et al. MicroRNAs of the miR-17 approximately 92 family are critical regulators of TFH differentiation. Nature Immunol. 14, 849–857 (2013).
Brannon-Peppas, L. & Blanchette, J. O. Nanoparticle and targeted systems for cancer therapy. Adv. Drug Deliv. Rev. 64, S206–S212 (2012).
Brigger, I., Dubernet, C. & Couvreur, P. Nanoparticles in cancer therapy and diagnosis. Adv. Drug Deliv. Rev. 64, S24–S36 (2012).
Jain, R. K. Delivery of molecular and cellular medicine to solid tumors. Adv. Drug. Deliv. Rev. 64, S353–S365 (2012).
Gilleron, J. et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nature Biotech. 31, 638–646 (2013).
Jopling, C. L., Yi, M., Lancaster, A. M., Lemon, S. M. & Sarnow, P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309, 1577–1581 (2005).
Lindow, M. & Kauppinen, S. Discovering the first microRNA-targeted drug. J. Cell Biol. 199, 407–412 (2012).
Iorio, M. V. & Croce, C. M. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol. Med. 4, 143–159 (2012).
Bouchie, A. First microRNA mimic enters clinic. Nature Biotech. 31, 577–577 (2013).
Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000).
Takamizawa, J. et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 64, 3753–3756 (2004).
Johnson, S. M. et al. RAS is regulated by the let-7 microRNA family. Cell 120, 635–647 (2005).
Mayr, C., Hemann, M. T. & Bartel, D. P. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315, 1576–1579 (2007).
Kumar, M. S. et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc. Natl Acad. Sci. USA 105, 3903–3908 (2008).
Esquela-Kerscher, A. et al. The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle 7, 759–764 (2008).
Yu, F. et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131, 1109–1123 (2007).
Volinia, S. et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA 103, 2257–2261 (2006).
Croce, C. M. Causes and consequences of microRNA dysregulation in cancer. Nature Rev. Genet. 10, 704–714 (2009).
Meng, F. et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133, 647–658 (2007).
Zhu, S., Si, M. L., Wu, H. & Mo, Y. Y. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J. Biol. Chem. 282, 14328–14336 (2007).
Asangani, I. A. et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27, 2128–2136 (2008).
Frankel, L. B. et al. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J. Biol. Chem. 283, 1026–1033 (2008).
Chau, B. N. et al. MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci. Transl. Med. 4, 121ra118 (2012).
van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).
Montgomery, R. L. et al. Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 124, 1537–1547 (2011).
Porrello, E. R. et al. miR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circ. Res. 109, 670–679 (2011).
Hullinger, T. G. et al. Inhibition of miR-15 protects against cardiac ischemic injury. Circ. Res. 110, 71–81 (2012).
Porrello, E. R. et al. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc. Natl Acad. Sci. USA 110, 187–192 (2013).
Fornari, F. et al. miR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 27, 5651–5661 (2008).
Gramantieri, L. et al. MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin. Cancer Res. 15, 5073–5081 (2009).
Pineau, P. et al. miR-221 overexpression contributes to liver tumorigenesis. Proc. Natl Acad. Sci. USA 107, 264–269 (2010).
Park, J. K. et al. miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res. 71, 7608–7616 (2011).
Trajkovski, M. et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011).
Khraiwesh, B. et al. Transcriptional control of gene expression by microRNAs. Cell 140, 111–122 (2010).
Eiring, A. M. et al. miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell 140, 652–665 (2010).
Braconi, C. et al. microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene 30, 4750–4756 (2011).
Taulli, R., Loretelli, C. & Pandolfi, P. P. From pseudo-ceRNAs to circ-ceRNAs: a tale of cross-talk and competition. Nature Struct. Mol. Biol. 20, 541–543 (2013).
Zisoulis, D. G., Kai, Z. S., Chang, R. K. & Pasquinelli, A. E. Autoregulation of microRNA biogenesis by let-7 and Argonaute. Nature 486, 541–544 (2012).
Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).
Tang, X., Li, M., Tucker, L. & Ramratnam, B. Glycogen synthase kinase 3 beta (GSK3β) phosphorylates the RNAase III enzyme Drosha at S300 and S302. PLoS ONE 6, e20391 (2011).
Wu, C. et al. Hypoxia potentiates microRNA-mediated gene silencing through posttranslational modification of Argonaute2. Mol. Cell. Biol. 31, 4760–4774 (2011).
Zeng, Y., Sankala, H., Zhang, X. & Graves, P. R. Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies. Biochem. J. 413, 429–436 (2008).
Heo, I. et al. Lin28 mediates the terminal uridylation of let-7 precursor microRNA. Mol. Cell 32, 276–284 (2008).
Acknowledgements
We are grateful to our colleague Dr R. Zhou and members of the Rana laboratory for helpful discussions. We apologize to our colleagues whose work we could not cite owing to space limitations. This work was supported in part by grants from the US National Institutes of Health (to T.M.R).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
FURTHER INFORMATION
Rights and permissions
About this article
Cite this article
Li, Z., Rana, T. Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov 13, 622–638 (2014). https://doi.org/10.1038/nrd4359
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrd4359