MicroRNAs (miRNAs) belong to class of small non-coding RNAs that are involved in development and diseases. miRNAs control gene expression by targeting mRNAs based on sequence complementarity.
miRNAs can serve as oncomiRs by targeting tumour suppressor mRNAs and as tumour suppressor miRNAs by targeting mRNAs that encode oncoproteins.
The deregulation of miRNAs in disease conditions can be harnessed as potential therapeutics by either miRNA replacement therapy using miRNA mimics or inhibition of miRNA function by antimiRs.
Two of the major focus areas in the development of miRNA therapeutics are enhancing the in vivo stability of therapeutic RNA molecules and designing optimal delivery systems for disease-specific release with minimal toxicity.
Numerous preclinical studies utilizing various disease models have tested the use of these new-generation therapeutics, and several miRNA-based therapeutics have advanced into clinical testing.
In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
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). Discovery of the first miRNA, lin-4, and elucidation of its function in development.
Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000). Discovery of the second miRNA, let-7, and description of its role of in the development of C. elegans.
Pasquinelli, A. E. et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408, 86–89 (2000).
Esteller, M. Non-coding RNAs in human disease. Nat. Rev. Genet. 12, 861–874 (2011).
Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).
Roush, S. & Slack, F. J. The let-7 family of microRNAs. Trends Cell Biol. 18, 505–516 (2008).
Iorio, M. V. & Croce, C. M. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol. Med. 4, 143–159 (2012).
Tili, E., Michaille, J. J. & Croce, C. M. MicroRNAs play a central role in molecular dysfunctions linking inflammation with cancer. Immunol. Rev. 253, 167–184 (2013).
Rupaimoole, R., Calin, G. A., Lopez-Berestein, G. & Sood, A. K. miRNA deregulation in cancer cells and the tumor microenvironment. Cancer Discov. 6, 235–246 (2016).
Gurha, P. MicroRNAs in cardiovascular disease. Curr. Opin. Cardiol. 31, 249–254 (2016).
Worringer, K. A. et al. The let-7/LIN-41 pathway regulates reprogramming to human induced pluripotent stem cells by controlling expression of prodifferentiation genes. Cell Stem Cell 14, 40–52 (2014).
Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).
Lin, S. & Gregory, R. I. MicroRNA biogenesis pathways in cancer. Nat. Rev. Cancer 15, 321–333 (2015).
Hill, D. A. et al. DICER1 mutations in familial pleuropulmonary blastoma. Science 325, 965 (2009).
Heravi-Moussavi, A. et al. Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N. Engl. J. Med. 366, 234–242 (2012). Evaluates mutations in the miRNA biogenesis enzyme Dicer in cancers using patient tumour samples.
Rakheja, D. et al. Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours. Nat. Commun. 2, 4802 (2014).
Melo, S. A. et al. A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells. Cancer Cell 18, 303–315 (2010). Identifies mutations in the exportin 5 enzyme in cancer cells.
Bader, A. G. miR-34 — a microRNA replacement therapy is headed to the clinic. Front. Genet. 3, 120 (2012).
Li, Z. & Rana, T. M. Therapeutic targeting of microRNAs: current status and future challenges. Nat. Rev. Drug Discov. 13, 622–638 (2014).
van Rooij, E. & Olson, E. N. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat. Rev. Drug Discov. 11, 860–872 (2012).
van Rooij, E. & Kauppinen, S. Development of microRNA therapeutics is coming of age. EMBO Mol. Med. 6, 851–864 (2014).
Karube, Y. et al. Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci. 96, 111–115 (2005).
Merritt, W. M. et al. Dicer, Drosha, and outcomes in patients with ovarian cancer. N. Engl. J. Med. 359, 2641–2650 (2008). A large study utilizing tumour samples to evaluate miRNA biogenesis enzyme Dicer and Drosha deregulations in cancer and the relationship to patient outcomes.
Wang, X., Zhao, X., Gao, P. & Wu, M. c-Myc modulates microRNA processing via the transcriptional regulation of Drosha. Sci. Rep. 3, 1942 (2013).
Allegra, D. et al. Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia. Leukemia 28, 98–107 (2014).
Torres, A. et al. Major regulators of microRNAs biogenesis Dicer and Drosha are down-regulated in endometrial cancer. Tumour Biol. 32, 769–776 (2011).
Dedes, K. J. et al. Down-regulation of the miRNA master regulators Drosha and Dicer is associated with specific subgroups of breast cancer. Eur. J. Cancer 47, 138–150 (2011).
Guo, X. et al. The microRNA-processing enzymes: Drosha and Dicer can predict prognosis of nasopharyngeal carcinoma. J. Cancer Res. Clin. Oncol. 138, 49–56 (2012).
Su, X. et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 467, 986–990 (2010). Documents the transcriptional regulation of Dicer in cancer.
Martello, G. et al. A microRNA targeting dicer for metastasis control. Cell 141, 1195–1207 (2010).
Tokumaru, S., Suzuki, M., Yamada, H., Nagino, M. & Takahashi, T. let-7 regulates Dicer expression and constitutes a negative feedback loop. Carcinogenesis 29, 2073–2077 (2008).
Rupaimoole, R. et al. Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression. Oncogene 35, 4312–4320 (2016).
van den Beucken, T. et al. Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER. Nat. Commun. 5, 5203 (2014).
Shen, J. et al. EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2. Nature 497, 383–387 (2013).
Zhang, X., Wan, G., Berger, F. G., He, X. & Lu, X. The ATM kinase induces microRNA biogenesis in the DNA damage response. Mol. Cell 41, 371–383 (2011).
Liu, C. et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat. Med. 17, 211–215 (2011).
Rokavec, M. et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J. Clin. Invest. 124, 1853–1867 (2014).
Okada, N. et al. A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression. Genes Dev. 28, 438–450 (2014).
Li, L. et al. MiR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1. Clin. Exp. Med. 13, 109–117 (2013).
Tarasov, V. et al. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 6, 1586–1593 (2007).
Chang, T. C. et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol. Cell 26, 745–752 (2007).
Raver-Shapira, N. et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol. Cell 26, 731–743 (2007).
Misso, G. et al. Mir-34: a new weapon against cancer? Mol. Ther. Nucleic Acids 3, e194 (2014).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Wang, X. et al. Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell. Signal. 27, 443–452 (2015).
Cortez, M. A. et al. PDL1 regulation by p53 via miR-34. J. Natl Cancer Inst. 108, djv303 (2016).
Yu, F. et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131, 1109–1123 (2007).
Johnson, C. D. et al. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res. 67, 7713–7722 (2007).
Brueckner, B. et al. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res. 67, 1419–1423 (2007).
Iliopoulos, D., Hirsch, H. A. & Struhl, K. An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).
Sung, S. Y. et al. Loss of let-7 microRNA upregulates IL-6 in bone marrow-derived mesenchymal stem cells triggering a reactive stromal response to prostate cancer. PLoS ONE 8, e71637 (2013).
Johnson, S. M. et al. RAS is regulated by the let-7 microRNA family. Cell 120, 635–647 (2005).
Newman, M. A., Thomson, J. M. & Hammond, S. M. Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 14, 1539–1549 (2008).
Gregory, P. A. et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 10, 593–601 (2008).
De Craene, B. & Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13, 97–110 (2013).
Korpal, M., Lee, E. S., Hu, G. & Kang, Y. The miR-200 family inhibits epithelial–mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J. Biol. Chem. 283, 14910–14914 (2008).
Park, S. M., Gaur, A. B., Lengyel, E. & Peter, M. E. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22, 894–907 (2008).
Burk, U. et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9, 582–589 (2008).
Gregory, P. A. et al. An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial–mesenchymal transition. Mol. Biol. Cell 22, 1686–1698 (2011).
Pecot, C. V. et al. Tumour angiogenesis regulation by the miR-200 family. Nat. Commun. 4, 2427 (2013).
Pekarsky, Y. & Croce, C. M. Role of miR-15/16 in CLL. Cell Death Differ. 22, 6–11 (2015).
Klein, U. et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17, 28–40 (2010).
Yang, D. et al. Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. Cancer Cell 23, 186–199 (2013).
Liu, G. et al. Augmentation of response to chemotherapy by microRNA-506 through regulation of RAD51 in serous ovarian cancers. J. Natl Cancer Inst. 107, djv108 (2015).
Liu, G. et al. MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6–FOXM1 axis in ovarian cancer. J. Pathol. 233, 308–318 (2014).
Keklikoglou, I. et al. MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways. Oncogene 31, 4150–4163 (2012).
Nishimura, M. et al. Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment. Cancer Discov. 3, 1302–1315 (2013).
Landen, C. N. Jr et al. Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res. 65, 6910–6918 (2005). First report of using neutral liposome DOPC for the delivery of small interfering RNAs (siRNAs) to tumours.
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).
Yan, L. X. et al. MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA 14, 2348–2360 (2008).
Li, Q. et al. MiR-21/Smad 7 signaling determines TGF-β1-induced CAF formation. Sci. Rep. 3, 2038 (2013).
Medina, P. P., Nolde, M. & Slack, F. J. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467, 86–90 (2010). Reports the concept of oncomiR addiction, whereby cancers tend to have a dependence on oncogenic miRNA expression.
Hatley, M. E. et al. Modulation of K-Ras-dependent lung tumorigenesis by microRNA-21. Cancer Cell 18, 282–293 (2010).
Krichevsky, A. M. & Gabriely, G. miR-21: a small multi-faceted RNA. J. Cell. Mol. Med. 13, 39–53 (2009).
Campbell, J. D. et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet. 48, 607–616 (2016).
Fujita, S. et al. miR-21 gene expression triggered by AP-1 is sustained through a double-negative feedback mechanism. J. Mol. Biol. 378, 492–504 (2008).
Iliopoulos, D., Jaeger, S. A., Hirsch, H. A., Bulyk, M. L. & Struhl, K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol. Cell 39, 493–506 (2010).
Gironella, M. et al. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc. Natl Acad. Sci. USA 104, 16170–16175 (2007).
O'Connell, R. M., Chaudhuri, A. A., Rao, D. S. & Baltimore, D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc. Natl Acad. Sci. USA 106, 7113–7118 (2009).
Faraoni, I., Antonetti, F. R., Cardone, J. & Bonmassar, E. miR-155 gene: a typical multifunctional microRNA. Biochim. Biophys. Acta 1792, 497–505 (2009).
Tili, E., Croce, C. M. & Michaille, J. J. miR-155: on the crosstalk between inflammation and cancer. Int. Rev. Immunol. 28, 264–284 (2009).
Tili, E. et al. Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer. Proc. Natl Acad. Sci. USA 108, 4908–4913 (2011).
Babar, I. A. et al. Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma. Proc. Natl Acad. Sci. USA 109, E1695–E1704 (2012).
Kong, W. et al. Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer. Oncogene 33, 679–689 (2014).
Kulshreshtha, R. et al. A microRNA signature of hypoxia. Mol. Cell. Biol. 27, 1859–1867 (2007). Reports that miR-210, a hypoxia marker miRNA, is significantly upregulated during hypoxia exposure.
Puissegur, M. P. et al. miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ. 18, 465–478 (2011).
Yang, W. et al. Downregulation of miR-210 expression inhibits proliferation, induces apoptosis and enhances radiosensitivity in hypoxic human hepatoma cells in vitro. Exp. Cell Res. 318, 944–954 (2012).
Fasanaro, P. et al. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J. Biol. Chem. 283, 15878–15883 (2008).
Crosby, M. E., Kulshreshtha, R., Ivan, M. & Glazer, P. M. MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Res. 69, 1221–1229 (2009).
Mogilyansky, E. & Rigoutsos, I. The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ. 20, 1603–1614 (2013).
O'Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V. & Mendell, J. T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).
Koralov, S. B. et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 132, 860–874 (2008).
Dews, M. et al. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat. Genet. 38, 1060–1065 (2006).
de Pontual, L. et al. Germline deletion of the miR-17 approximately 92 cluster causes skeletal and growth defects in humans. Nat. Genet. 43, 1026–1030 (2011).
Marcelis, C. L. et al. Genotype–phenotype correlations in MYCN-related Feingold syndrome. Hum. Mutat. 29, 1125–1132 (2008).
Ma, L., Teruya-Feldstein, J. & Weinberg, R. A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007).
Bloomston, M. et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297, 1901–1908 (2007).
Saldanha, G. et al. microRNA-10b is a prognostic biomarker for melanoma. Mod. Pathol. 29, 112–121 (2016).
Ma, L. et al. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat. Biotechnol. 28, 341–347 (2010). A study that uses antimiR against miR-10b to suppress miR-10b function and demonstrates significant reduction in breast cancer metastasis.
Nakayama, I. et al. Loss of HOXD10 expression induced by upregulation of miR-10b accelerates the migration and invasion activities of ovarian cancer cells. Int. J. Oncol. 43, 63–71 (2013).
Garofalo, M. et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 16, 498–509 (2009).
le Sage, C. et al. Regulation of the p27Kip1 tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J. 26, 3699–3708 (2007).
Pineau, P. et al. miR-221 overexpression contributes to liver tumorigenesis. Proc. Natl Acad. Sci. USA 107, 264–269 (2010).
Wiggins, J. F. et al. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res. 70, 5923–5930 (2010).
Trang, P. et al. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol. Ther. 19, 1116–1122 (2011).
Pramanik, D. et al. Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Mol. Cancer Ther. 10, 1470–1480 (2011).
Kasinski, A. L. & Slack, F. J. miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma. Cancer Res. 72, 5576–5587 (2012).
Stahlhut, C. & Slack, F. J. Combinatorial action of microRNAs let-7 and miR-34 effectively synergizes with erlotinib to suppress non-small cell lung cancer cell proliferation. Cell Cycle 14, 2171–2180 (2015).
Cortez, M. A. et al. Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer. Mol. Ther. 22, 1494–1503 (2014).
Kota, J. et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137, 1005–1017 (2009).
Ji, J. et al. MicroRNA expression, survival, and response to interferon in liver cancer. N. Engl. J. Med. 361, 1437–1447 (2009).
Calin, G. A. et al. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc. Natl Acad. Sci. USA 105, 5166–5171 (2008).
Reid, G. et al. Abstract 3976: targeted delivery of a synthetic microRNA-based mimic as an approach to cancer therapy. Cancer Res. 75, abstr. 3976 (2015).
Gabriely, G. et al. Human glioma growth is controlled by microRNA-10b. Cancer Res. 71, 3563–3572 (2011).
Yoo, B. et al. Combining miR-10b-targeted nanotherapy with low-dose doxorubicin elicits durable regressions of metastatic breast cancer. Cancer Res. 75, 4407–4415 (2015).
Park, J. K. et al. miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res. 71, 7608–7616 (2011).
Cheng, C. J. et al. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 518, 107–110 (2015).
Reshetnyak, Y. K., Andreev, O. A., Lehnert, U. & Engelman, D. M. Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix. Proc. Natl Acad. Sci. USA 103, 6460–6465 (2006).
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).
Thibault, P. A. et al. Regulation of hepatitis C virus genome replication by Xrn1 and microRNA-122 binding to individual sites in the 5′ untranslated region. J. Virol. 89, 6294–6311 (2015).
Luna, J. M. et al. Hepatitis C virus RNA functionally sequesters miR-122. Cell 160, 1099–1110 (2015). A study that records the functional role of HCV RNA sequestration of miR-122 and relevance to therapy (read along with references 124 and 125).
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).
Elmen, J. et al. LNA-mediated microRNA silencing in non-human primates. Nature 452, 896–899 (2008).
Hsu, S. H. et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J. Clin. Invest. 122, 2871–2883 (2012).
Tsai, W. C. et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J. Clin. Invest. 122, 2884–2897 (2012).
Krutzfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438, 685–689 (2005).
Cheng, Y. & Zhang, C. MicroRNA-21 in cardiovascular disease. J. Cardiovasc. Transl. Res. 3, 251–255 (2010).
Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).
Chau, B. N. et al. MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci. Transl. Med. 4, 121ra18 (2012).
Xin, M. et al. MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Genes Dev. 23, 2166–2178 (2009).
Boettger, T. et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J. Clin. Invest. 119, 2634–2647 (2009).
Davis-Dusenbery, B. N. et al. Down-regulation of Kruppel-like factor-4 (KLF4) by microRNA-143/145 is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor-β and bone morphogenetic protein 4. J. Biol. Chem. 286, 28097–28110 (2011).
Cordes, K. R. et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 460, 705–710 (2009).
Ikeda, S. et al. MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes. Mol. Cell. Biol. 29, 2193–2204 (2009).
Shan, Z. X. et al. Upregulated expression of miR-1/miR-206 in a rat model of myocardial infarction. Biochem. Biophys. Res. Commun. 381, 597–601 (2009).
Grueter, C. E. et al. A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Cell 149, 671–683 (2012).
Montgomery, R. L. et al. Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 124, 1537–1547 (2011).
Montgomery, R. L. et al. MicroRNA mimicry blocks pulmonary fibrosis. EMBO Mol. Med. 6, 1347–1356 (2014).
Rayner, K. J. et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328, 1570–1573 (2010).
Davalos, A. et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc. Natl Acad. Sci. USA 108, 9232–9237 (2011).
Rayner, K. J. et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 478, 404–407 (2011).
Goedeke, L. et al. Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice. EMBO Mol. Med. 6, 1133–1141 (2014).
Belgardt, B. F. et al. The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes. Nat. Med. 21, 619–627 (2015).
McArthur, K., Feng, B., Wu, Y., Chen, S. & Chakrabarti, S. MicroRNA-200b regulates vascular endothelial growth factor-mediated alterations in diabetic retinopathy. Diabetes 60, 1314–1323 (2011).
Wang, B. et al. E-Cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-β. Diabetes 59, 1794–1802 (2010).
Slusarz, A. & Pulakat, L. The two faces of miR-29. J. Cardiovasc. Med. (Hagerstown) 16, 480–490 (2015).
Roggli, E. et al. Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice. Diabetes 61, 1742–1751 (2012).
Maurer, B. et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 62, 1733–1743 (2010).
Janssen, H. L. et al. Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 368, 1685–1694 (2013).
Ottosen, S. et al. In vitro antiviral activity and preclinical and clinical resistance profile of miravirsen, a novel anti-hepatitis C virus therapeutic targeting the human factor miR-122. Antimicrob. Agents Chemother. 59, 599–608 (2015).
Hong. D. S. et al. MRX34, a liposomal miR-34 mimic, in patients with advanced solid tumors: Final dose-escalation results from a first-in-human phase I trial of microRNA therapy. J. Clin. Oncol. 34, (Suppl), abstr. 2508 (2015).
Beg, M. S. et al. Abstract C43: safety, tolerability, and clinical activity of MRX34, the first-in-class liposomal miR-34 mimic, in patients with advanced solid tumors. Mol. Cancer Ther. 14, abstr. C43 (2015). Highlights the clinical safety and activity data of MRX34, a miR-34 mimic-based therapy against cancers.
van Zandwijk, N. et al. P1.02: MesomiR 1: a phase I study of TargomiRs in patients with refractory malignant pleural mesothelioma (MPM) and lung cancer (NSCLC). Ann. Oncol. 26 (Suppl. 2), ii16 (2015).
Trajkovski, M. et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011).
Cheng, C. J. & Slack, F. J. The duality of oncomiR addiction in the maintenance and treatment of cancer. Cancer J. 18, 232–237 (2012).
Rupaimoole, R., Han, H. D., Lopez-Berestein, G. & Sood, A. K. MicroRNA therapeutics: principles, expectations, and challenges. Chin. J. Cancer 30, 368–370 (2011).
Vaupel, P. & Mayer, A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 26, 225–239 (2007).
Rupaimoole, R. et al. Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression. Nat. Commun. 5, 5202 (2014).
Imig, J. et al. miR-CLIP capture of a miRNA targetome uncovers a lincRNA H19–miR-106a interaction. Nat. Chem. Biol. 11, 107–114 (2015).
Chou, C. H. et al. miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res. 44, D239–D247 (2016).
Li, J. H., Liu, S., Zhou, H., Qu, L. H. & Yang, J. H. starBase v2.0: decoding miRNA–ceRNA, miRNA–ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 42, D92–D97 (2014).
Agarwal, V., Bell, G. W., Nam, J. W. & Bartel, D. P. Predicting effective microRNA target sites in mammalian mRNAs. eLife 4, e05005 (2015).
Eulalio, A. et al. Functional screening identifies miRNAs inducing cardiac regeneration. Nature 492, 376–381 (2012).
Kovalchuk, O. et al. Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol. Cancer Ther. 7, 2152–2159 (2008).
Sun, L. et al. MiR-200b and miR-15b regulate chemotherapy-induced epithelial–mesenchymal transition in human tongue cancer cells by targeting BMI1. Oncogene 31, 432–445 (2012).
Geary, R. S. et al. Pharmacokinetic properties of 2′-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats. J. Pharmacol. Exp. Ther. 296, 890–897 (2001).
Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell. Metab. 3, 87–98 (2006).
Reshetnyak, Y. K., Andreev, O. A., Segala, M., Markin, V. S. & Engelman, D. M. Energetics of peptide (pHLIP) binding to and folding across a lipid bilayer membrane. Proc. Natl Acad. Sci. USA 105, 15340–15345 (2008).
Kulkarni, R. K., Moore, E. G., Hegyeli, A. F. & Leonard, F. Biodegradable poly(lactic acid) polymers. J. Biomed. Mater. Res. 5, 169–181 (1971).
Blum, J. S. & Saltzman, W. M. High loading efficiency and tunable release of plasmid DNA encapsulated in submicron particles fabricated from PLGA conjugated with poly-L-lysine. J. Control. Release 129, 66–72 (2008).
Yang, X. Z. et al. Systemic delivery of siRNA with cationic lipid assisted PEG-PLA nanoparticles for cancer therapy. J. Control. Release 156, 203–211 (2011).
Ozpolat, B., Sood, A. K. & Lopez-Berestein, G. Nanomedicine based approaches for the delivery of siRNA in cancer. J. Intern. Med. 267, 44–53 (2010).
Joshi, H. P. et al. Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis. Proc. Natl Acad. Sci. USA 111, 5331–5336 (2014).
MacDiarmid, J. A. et al. Bacterially derived 400 nm particles for encapsulation and cancer cell targeting of chemotherapeutics. Cancer Cell 11, 431–445 (2007).
Taylor, K. et al. Nanocell targeting using engineered bispecific antibodies. MAbs 7, 53–65 (2015).
Akhtar, S. & Benter, I. F. Nonviral delivery of synthetic siRNAs in vivo. J. Clin. Invest. 117, 3623–3632 (2007).
Duncan, R. & Izzo, L. Dendrimer biocompatibility and toxicity. Adv. Drug Deliv. Rev. 57, 2215–2237 (2005).
Gonzalez, H., Hwang, S. J. & Davis, M. E. New class of polymers for the delivery of macromolecular therapeutics. Bioconjug. Chem. 10, 1068–1074 (1999).
Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010). Study reports data on first in-human clinical trial involving siRNA-based therapeutics against cancer.
Kim, S. H., Jeong, J. H., Lee, S. H., Kim, S. W. & Park, T. G. PEG conjugated VEGF siRNA for anti-angiogenic gene therapy. J. Control. Release 116, 123–129 (2006).
Ragelle, H., Vandermeulen, G. & Preat, V. Chitosan-based siRNA delivery systems. J. Control. Release 172, 207–218 (2013).
Nair, J. K. et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136, 16958–16961 (2014).
Dimitrova, N. et al. Stromal expression of miR-143/145 promotes neoangiogenesis in lung cancer development. Cancer Discov. 6, 188–201 (2016).
Suzuki, H. I., Katsura, A., Matsuyama, H. & Miyazono, K. MicroRNA regulons in tumor microenvironment. Oncogene 34, 3085–3094 (2015).
Frediani, J. N. & Fabbri, M. Essential role of miRNAs in orchestrating the biology of the tumor microenvironment. Mol. Cancer 15, 42 (2016).
Bronisz, A. et al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat. Cell Biol. 14, 159–167 (2011).
Mitra, A. K. et al. MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer. Cancer Discov. 2, 1100–1108 (2012).
Ibrahim, A. F. et al. MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma. Cancer Res. 71, 5214–5224 (2011).
Pramanik, D. et al. Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Mol. Cancer Ther. 10, 1470–1480 (2011).
Putta, S. et al. Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J. Am. Soc. Nephrol. 23, 458–469 (2012).
Long, J., Wang, Y., Wang, W., Chang, B. H. & Danesh, F. R. MicroRNA-29c is a signature microRNA under high glucose conditions that targets Sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy. J. Biol. Chem. 286, 11837–11848 (2011).
Hullinger, T. G. et al. Inhibition of miR-15 protects against cardiac ischemic injury. Circ. Res. 110, 71–81 (2012).
The authors thank L. Jacob and A. Jiao for helpful comments on this manuscript. The authors acknowledge support from the Ludwig Center at Harvard, Boston, Massachusetts, USA, and grants from the US National Institutes of Health (R01 CA157749; P50 CA177444).
F.J.S is an adviser to Mirna Therapeutics and miRagen Therapeutics. R.R. declares no competing interests.
- Non-coding RNA
Naturally transcribed RNA molecule that does not encode any protein. Family members include microRNAs and long non-coding RNAs.
- miRNA mimics
(MicroRNA mimics). Synthetically derived small RNA molecule duplexes, which, upon introduction into the cells, behave similarly to endogenous miRNAs.
Also called microRNA (miRNA) inhibitors, antimiRs are small, synthetically derived molecules, which have sequence complementary to target mature miRNAs. They are known to sequester target miRNAs and are used to suppress miRNA function.
About this article
Cite this article
Rupaimoole, R., Slack, F. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16, 203–222 (2017). https://doi.org/10.1038/nrd.2016.246
Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer
Genome Medicine (2021)
CircTM7SF3 contributes to oxidized low-density lipoprotein-induced apoptosis, inflammation and oxidative stress through targeting miR-206/ASPH axis in atherosclerosis cell model in vitro
BMC Cardiovascular Disorders (2021)
Potential treatment for chronic myeloid leukemia using microRNA: in silico comparison between plants and human microRNAs in targeting BCR-ABL1 gene
Egyptian Journal of Medical Human Genetics (2021)
miR-636 inhibits EMT, cell proliferation and cell cycle of ovarian cancer by directly targeting transcription factor Gli2 involved in Hedgehog pathway
Cancer Cell International (2021)
MicroRNA-3613-3p functions as a tumor suppressor and represents a novel therapeutic target in breast cancer
Breast Cancer Research (2021)