Table Info

Table 1.

List of miRNAs based therapeutics in their clinical trials

Therapeutics based on miRNAs and names of companies	Therapeutic agent	The system used for delivery	Disease targeted	Stage of clinical trial	Gov identifier of clinical trial
Miravirsen (Santaris Pharma)	AntimiR-122	Antisense inhibitor with LNA modification	Chronic hepatitis C	Phase I is completed	NCT00688012, NCT00979927, NCT01646489
RG-101 (Regulus-therapeutics)	AntimiR-122	AntimiR conjugated with GalNac	Chronic hepatitis C	Phase II is completed	EudraCT numbers 2015-001535-21, 2015-004702-42
RG-125/AZD4076 (Regulus-therapeutics)	AntimiR-103/107	AntimiR conjugated with GalNac	Patient with type 2 diabetes	Phase I is completed	NCT02612662, NCT02826525
MRG-106 (miRagen-therapeutics)	AntimiR-155	Antisense inhibitor with LNA modification	Mycosis fungoides and cutaneous T cell lymphoma	Phase I is completed	NCT02580552
MRG-201 (miRagen-therapeutics)	miR-29 mimic	miRNA duplex with cholesterol conjugation	Scleroderma	Phase II is completed	NCT02603224
MesomiR-1 (EnGeneIC)	miR-16 mimic	Delivery vehicle of EnGeneIC	Mesothelioma and NSCLC	Phase I is completed	NCT02369198
MRX34 (miRNA therapeutics)	miR-34 mimic	Lipid nanoparticles	Multiple-solid tumors	Phase I is terminated	NCT01829971

EudraCT numbered trials are registered at EU Clinical Trials Register (clinicaltrialsregister.eu). Gov: government; LNA: locked nucleic acid; NSCLC: non-small cell lung cancer; GalNac: N-acetyl-galactosamine

Declarations

Acknowledgments

We are thankful to the Department of Biotechnology Jaypee Institute of Information Technology, NOIDA, INDIA for providing the technical support.

Author contributions

CKJ and PS contributed in design of the work, analysis, interpretation of data, writing - original draft, and writing - review & editing; CKJ also contributed in supervision and conceptualization; AKP, NS, RSK contributed in data curation, validation, and visualization; All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33. [DOI] [PubMed] [PMC]

Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15:509–24. [DOI] [PubMed]

Bayraktar R, Pichler M, Kanlikilicer P, Ivan C, Bayraktar E, Kahraman N, et al. MicroRNA 603 acts as a tumor suppressor and inhibits triple-negative breast cancer tumorigenesis by targeting elongation factor 2 kinase. Oncotarget. 2017;8:11641–58. [DOI] [PubMed] [PMC]

Kanlikilicer P, Rashed MH, Bayraktar R, Mitra R, Ivan C, Aslan B, et al. Ubiquitous release of exosomal tumor suppressor miR-6126 from ovarian cancer cells. Cancer Res. 2016;76:7194–207. Erratum in: Cancer Res. 2018;78:3402. [DOI] [PubMed] [PMC]

Mangala LS, Wang H, Jiang D, Wu SY, Somasunderam A, Volk DE, et al. Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy. JCI Insight. 2016;1:e87754. Erratum in: JCI Insight. 2021;6:e149896. [DOI] [PubMed] [PMC]

Rashed MH, Kanlikilicer P, Rodriguez-Aguayo C, Pichler M, Bayraktar R, Bayraktar E, et al. Exosomal miR-940 maintains SRC-mediated oncogenic activity in cancer cells: a possible role for exosomal disposal of tumor suppressor miRNAs. Oncotarget. 2017;8:20145–64. [DOI] [PubMed] [PMC]

Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet. 2005;37:766–70. [DOI] [PubMed]

Calin GA, Croce CM. MicroRNAs and chromosomal abnormalities in cancer cells. Oncogene. 2006;25:6202–10. [DOI] [PubMed]

Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002;99:15524–9. [DOI] [PubMed] [PMC]

10.

Van Roosbroeck K, Calin GA. MicroRNAs in chronic lymphocytic leukemia: miRacle or miRage for prognosis and targeted therapies? Semin Oncol. 2016;43:209–14. [DOI] [PubMed] [PMC]

11.

Van Roosbroeck K, Pollet J, Calin GA. miRNAs and long noncoding RNAs as biomarkers in human diseases. Expert Rev Mol Diagn. 2013;13:183–204. [DOI] [PubMed]

12.

Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–22. [DOI] [PubMed]

13.

Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov. 2013;12:847–65. [DOI] [PubMed] [PMC]

14.

Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An overview of microRNAs: biology, functions, therapeutics, and analysis methods. J Cell Physiol. 2019;234:5451–65. [DOI] [PubMed]

15.

Vishnoi A, Rani S. MiRNA biogenesis and regulation of diseases: an overview. Methods Mol Biol. 2017;1509:1–10. [DOI] [PubMed]

16.

Yan H, Bu P. Non-coding RNA in cancer. Essays Biochem. 2021;65:625–39. [DOI] [PubMed] [PMC]

17.

Li F. Expression and correlation of miR-124 and miR-126 in breast cancer. Oncol Lett. 2019;17:5115–9. [DOI] [PubMed] [PMC]

18.

Ebrahimi F, Gopalan V, Wahab R, Lu CT, Smith RA, Lam AK. Deregulation of miR-126 expression in colorectal cancer pathogenesis and its clinical significance. Exp Cell Res. 2015;339:333–41. [DOI] [PubMed]

19.

Esquela-Kerscher A, Slack FJ. Oncomirs–microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69. [DOI] [PubMed]

20.

Karube Y, Tanaka H, Osada H, Tomida S, Tatematsu Y, Yanagisawa K, et al. Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci. 2005;96:111–5. [DOI] [PubMed]

21.

Carmell MA, Xuan Z, Zhang MQ, Hannon GJ. The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes Dev. 2002;16:2733–42. [DOI] [PubMed]

22.

Nelson P, Kiriakidou M, Sharma A, Maniataki E, Mourelatos Z. The microRNA world: small is mighty. Trends Biochem Sci. 2003;28:534–40. [DOI] [PubMed]

23.

Medina PP, Nolde M, Slack FJ. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature. 2010;467:86–90. [DOI] [PubMed]

24.

Zhang L, Ge Y, Fuchs E. miR-125b can enhance skin tumor initiation and promote malignant progression by repressing differentiation and prolonging cell survival. Genes Dev. 2014;28:2532–46. [DOI] [PubMed] [PMC]

25.

Matsubara H, Takeuchi T, Nishikawa E, Yanagisawa K, Hayashita Y, Ebi H, et al. Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92. Oncogene. 2007;26:6099–105. [DOI] [PubMed]

26.

Marsolier J, Pineau S, Medjkane S, Perichon M, Yin Q, Flemington E, et al. OncomiR addiction is generated by a miR-155 feedback loop in Theileria-transformed leukocytes. PLoS Pathog. 2013;9:e1003222. [DOI] [PubMed] [PMC]

27.

Garrido-Cano I, Pattanayak B, Adam-Artigues A, Lameirinhas A, Torres-Ruiz S, Tormo E, et al. MicroRNAs as a clue to overcome breast cancer treatment resistance. Cancer Metastasis Rev. 2022;41:77–105. [DOI] [PubMed] [PMC]

28.

Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D, et al. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res. 2010;70:5923–30. [DOI] [PubMed] [PMC]

29.

Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17:211–5. [DOI] [PubMed] [PMC]

30.

Trang P, Wiggins JF, Daige CL, Cho C, Omotola M, Brown D, et al. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol Ther. 2011;19:1116–22. [DOI] [PubMed] [PMC]

31.

Pramanik D, Campbell NR, Karikari C, Chivukula R, Kent OA, Mendell JT, et al. Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Mol Cancer Ther. 2011;10:1470–80. [DOI] [PubMed] [PMC]

32.

Stahlhut C, Slack FJ. Combinatorial action of microRNAs let-7 and miR-34 effectively synergizes with erlotinib to suppress non-small cell lung cancer cell proliferation. Cell Cycle. 2015;14:2171–80. [DOI] [PubMed] [PMC]

33.

Pecot CV, Rupaimoole R, Yang D, Akbani R, Ivan C, Lu C, et al. Tumour angiogenesis regulation by the miR-200 family. Nat Commun. 2013;4:2427. [DOI] [PubMed] [PMC]

34.

Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009;137:1005–17. [DOI] [PubMed] [PMC]

35.

Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med. 2009;361:1437–47. [DOI] [PubMed] [PMC]

36.

Yang D, Sun Y, Hu L, Zheng H, Ji P, Pecot CV, et al. Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. Cancer Cell. 2013;23:186–99. Erratum in: Cancer Cell. 2013;23:705. [DOI] [PubMed] [PMC]

37.

Nishimura M, Jung EJ, Shah MY, Lu C, Spizzo R, Shimizu M, et al. Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment. Cancer Discov. 2013;3:1302–15. [DOI] [PubMed] [PMC]

38.

Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M, et al. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A. 2008;105:5166–71. [DOI] [PubMed] [PMC]

39.

Reid G, Williams M, Kirschner MB, Mugridge N, Weiss J, Brahmbhatt H, et al. Targeted delivery of a synthetic microRNA-based mimic as an approach to cancer therapy [abstract]. Cancer Res. 2015;75:3976. [DOI]

40.

Ma L, Reinhardt F, Pan E, Soutschek J, Bhat B, Marcusson EG, et al. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat Biotechnol. 2010;28:341–7. [DOI] [PubMed] [PMC]

41.

Gabriely G, Yi M, Narayan RS, Niers JM, Wurdinger T, Imitola J, et al. Human glioma growth is controlled by microRNA-10b. Cancer Res. 2011;71:3563–72. [DOI] [PubMed] [PMC]

42.

Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell. 2009;16:498–509. [DOI] [PubMed] [PMC]

43.

Le Sage C, Nagel R, Egan DA, Schrier M, Mesman E, Mangiola A, et al. Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J. 2007;26:3699–708. [DOI] [PubMed] [PMC]

44.

Park JK, Kogure T, Nuovo GJ, Jiang J, He L, Kim JH, et al. miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res. 2011;71:7608–16. [DOI] [PubMed] [PMC]

45.

Babar IA, Cheng CJ, Booth CJ, Liang X, Weidhaas JB, Saltzman WM, et al. Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma. Proc Natl Acad Sci U S A. 2012;109:E1695–704. [DOI] [PubMed] [PMC]

46.

Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C, et al. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature. 2015;518:107–10. [DOI] [PubMed] [PMC]

47.

Reshetnyak YK, Andreev OA, Lehnert U, Engelman DM. Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix. Proc Natl Acad Sci U S A. 2006;103:6460–5. [DOI] [PubMed] [PMC]

48.

Rupaimoole R, Ivan C, Yang D, Gharpure KM, Wu SY, Pecot CV, et al. Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression. Oncogene. 2016;35:4312–20. [DOI] [PubMed] [PMC]

49.

Monga I, Kumar M. Computational resources for prediction and analysis of functional miRNA and their targetome. Methods Mol Biol. 2019;1912:215–50. [DOI] [PubMed]

50.

Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 2011;39:D152–7. [DOI] [PubMed] [PMC]

51.

Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 2006;34:D140–4. [DOI] [PubMed] [PMC]

52.

Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2014;42:D68–73. [DOI] [PubMed] [PMC]

53.

Zhang Z, Yu J, Li D, Zhang Z, Liu F, Zhou X, et al. PMRD: plant microRNA database. Nucleic Acids Res. 2010;38:D806–13. [DOI] [PubMed] [PMC]

54.

Dai E, Yu X, Zhang Y, Meng F, Wang S, Liu X, et al. EpimiR: a database of curated mutual regulation between miRNAs and epigenetic modifications. Database (Oxford). 2014;2014:bau023. [DOI] [PubMed] [PMC]

55.

Qureshi A, Thakur N, Monga I, Thakur A, Kumar M. VIRmiRNA: a comprehensive resource for experimentally validated viral miRNAs and their targets. Database (Oxford). 2014;2014:bau103. [DOI] [PubMed] [PMC]

56.

Kiezun A, Artzi S, Modai S, Volk N, Isakov O, Shomron N. miRviewer: a multispecies microRNA homologous viewer. BMC Res Notes. 2012;5:92. [DOI] [PubMed] [PMC]

57.

Van Peer G, Lefever S, Anckaert J, Beckers A, Rihani A, Van Goethem A, et al. miRBase Tracker: keeping track of microRNA annotation changes. Database (Oxford). 2014;2014:bau080. [DOI] [PubMed] [PMC]

58.

Fromm B, Billipp T, Peck LE, Johansen M, Tarver JE, King BL, et al. A uniform system for the annotation of vertebrate microRNA genes and the evolution of the human microRNAome. Annu Rev Genet. 2015;49:213–42. [DOI] [PubMed] [PMC]

59.

Gerlach D, Kriventseva EV, Rahman N, Vejnar CE, Zdobnov EM. miROrtho: computational survey of microRNA genes. Nucleic Acids Res. 2009;37:D111–7. [DOI] [PubMed] [PMC]

60.

Maselli V, Di Bernardo D, Banfi S. CoGemiR: a comparative genomics microRNA database. BMC Genomics. 2008;9:457. [DOI] [PubMed] [PMC]

61.

Kaya KD, Karakülah G, Yakicier CM, Acar AC, Konu O. mESAdb: microRNA expression and sequence analysis database. Nucleic Acids Res. 2011;39:D170–80. [DOI] [PubMed] [PMC]

62.

Cheng WC, Chung IF, Tsai CF, Huang TS, Chen CY, Wang SC, et al. YM500v2: a small RNA sequencing (smRNA-seq) database for human cancer miRNome research. Nucleic Acids Res. 2015;43:D862–7. [DOI] [PubMed] [PMC]

63.

Szczesniak MW, Makalowska I. miRNEST 2.0: a database of plant and animal microRNAs. Nucleic Acids Res. 2014;42:D74–7. [DOI] [PubMed] [PMC]

64.

Vergoulis T, Kanellos I, Kostoulas N, Georgakilas G, Sellis T, Hatzigeorgiou A, et al. mirPub: a database for searching microRNA publications. Bioinformatics. 2015;31:1502–4. [DOI] [PubMed] [PMC]

65.

Zielezinski A, Dolata J, Alaba S, Kruszka K, Pacak A, Swida-Barteczka A, et al. mirEX 2.0–an integrated environment for expression profiling of plant microRNAs. BMC Plant Biol. 2015;15:144. [DOI] [PubMed] [PMC]

66.

Gong J, Wu Y, Zhang X, Liao Y, Sibanda VL, Liu W, et al. Comprehensive analysis of human small RNA sequencing data provides insights into expression profiles and miRNA editing. RNA Biol. 2014;11:1375–85. [DOI] [PubMed] [PMC]

67.

Juzenas S, Venkatesh G, Hübenthal M, Hoeppner MP, Du ZG, Paulsen M, et al. A comprehensive, cell specific microRNA catalogue of human peripheral blood. Nucleic Acids Res. 2017;45:9290–301. [DOI] [PubMed] [PMC]

68.

Barupal JK, Saini AK, Chand T, Meena A, Beniwal S, Suthar JR, et al. ExcellmiRDB for translational genomics: a curated online resource for extracellular microRNAs. OMICS. 2015;19:24–30. [DOI] [PubMed]

69.

Russo F, Di Bella S, Nigita G, Macca V, Laganà A, Giugno R, et al. miRandola: extracellular circulating microRNAs database. PLoS One. 2012;7:e47786. [DOI] [PubMed] [PMC]

70.

Yang Q, Qiu C, Yang J, Wu Q, Cui Q. miREnvironment database: providing a bridge for microRNAs, environmental factors and phenotypes. Bioinformatics. 2011;27:3329–30. [DOI] [PubMed]

71.

Gurjar AKS, Panwar AS, Gupta R, Mantri SS. PmiRExAt: plant miRNA expression atlas database and web applications. Database (Oxford). 2016;2016:baw060. [DOI] [PubMed] [PMC]

72.

Kumar Gupta A, Kumar M. HPVbase–a knowledgebase of viral integrations, methylation patterns and microRNAs aberrant expression: as potential biomarkers for Human papillomaviruses mediated carcinomas. Sci Rep. 2015;5:12522. [DOI] [PubMed] [PMC]

73.

Vergoulis T, Vlachos IS, Alexiou P, Georgakilas G, Maragkakis M, Reczko M, et al. TarBase 6.0: capturing the exponential growth of miRNA targets with experimental support. Nucleic Acids Res. 2012;40:D222–9. [DOI] [PubMed] [PMC]

74.

Hsu SD, Lin FM, Wu WY, Liang C, Huang WC, Chan WL, et al. miRTarBase: a database curates experimentally validated microRNA-target interaction. Nucleic Acids Res. 2011;39:D163–9. [DOI] [PubMed] [PMC]

75.

Chou CH, Chang NW, Shrestha S, Hsu SD, Lin YL, Lee WH, et al. miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res. 2016;44:D239–47. [DOI] [PubMed] [PMC]

76.

Andrés-León E, González Peña D, Gómez-López G, Pisano DG. miRGate: a curated database of human, mouse and rat miRNA–mRNA targets. Database (Oxford). 2015;2015:bav035. [DOI] [PubMed] [PMC]

77.

Yi X, Zhang Z, Ling Y, Xu W, Su Z. PNRD: a plant non-coding RNA database. Nucleic Acids Res. 2015;43:D982–9. [DOI] [PubMed] [PMC]

78.

Xiao F, Zuo Z, Cai G, Kang S, Gao X, Li T. miRecords: an integrated resource for microRNA-target interactions. Nucleic Acids Res. 2009;37:D105–10. [DOI] [PubMed] [PMC]

79.

Dweep H, Sticht C, Pandey P, Gretz N. miRWalk-database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Inform. 2011;44:839–47. [DOI] [PubMed]

80.

Lu TP, Lee CY, Tsai MH, Chiu YC, Hsiao CK, Lai LC, et al. miRSystem: an integrated system for characterizing enriched functions and pathways of microRNA targets. PLoS One. 2012;7:e42390. [DOI] [PubMed] [PMC]

81.

Piriyapongsa J, Bootchai C, Ngamphiw C, Tongsima S. microPIR2: a comprehensive database for human-mouse comparative study of microRNA-promoter interactions. Database (Oxford). 2014;2014:bau115. [DOI] [PubMed] [PMC]

82.

Hsu PWC, Lin LZ, Hsu SD, Hsu JBK, Huang HD. ViTa: prediction of host microRNAs targets on viruses. Nucleic Acids Res. 2007;35:D381–5. [DOI] [PubMed] [PMC]

83.

Hsu JBK, Chiu CM, Hsu SD, Huang WY, Chien CH, Lee TY, et al. miRTar: an integrated system for identifying miRNA-target interactions in human. BMC Bioinformatics. 2011;12:300. [DOI] [PubMed] [PMC]

84.

Paraskevopoulou MD, Georgakilas G, Kostoulas N, Vlachos IS, Vergoulis T, Reczko M, et al. DIANA-microT web server v5.0: service integration into miRNA functional analysis workflows. Nucleic Acids Res. 2013;41:W169–73. [DOI] [PubMed] [PMC]

85.

Wang X. miRDB: a microRNA target prediction and functional annotation database with a wiki interface. RNA. 2008;14:1012–7. [DOI] [PubMed] [PMC]

86.

Wong N, Wang X. miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res. 2015;43:D146–52. [DOI] [PubMed] [PMC]

87.

Ru Y, Kechris KJ, Tabakoff B, Hoffman P, Radcliffe RA, Bowler R, et al. The multiMiR R package and database: integration of microRNA-target interactions along with their disease and drug associations. Nucleic Acids Res. 2014;42:e133. [DOI] [PubMed] [PMC]

88.

Wu WS, Tu BW, Chen TT, Hou SW, Tseng JT. CSmiRTar: Condition-Specific microRNA targets database. PLoS One. 2017;12:e0181231. [DOI] [PubMed] [PMC]

89.

Bruno AE, Li L, Kalabus JL, Pan Y, Yu A, Hu Z. miRdSNP: a database of disease-associated SNPs and microRNA target sites on 3’UTRs of human genes. BMC Genomics. 2012;13:44. [DOI] [PubMed] [PMC]

90.

Bhattacharya A, Ziebarth JD, Cui Y. PolymiRTS database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways. Nucleic Acids Res. 2014;42:D86–91. [DOI] [PubMed] [PMC]

91.

Ziebarth JD, Bhattacharya A, Chen A, Cui Y. PolymiRTS database 2.0: linking polymorphisms in microRNA target sites with human diseases and complex traits. Nucleic Acids Res. 2012;40:D216–21. [DOI] [PubMed] [PMC]

92.

Yang Z, Ren F, Liu C, He S, Sun G, Gao Q, et al. dbDEMC: a database of differentially expressed miRNAs in human cancers. BMC Genomics. 2010;11:S5. [DOI] [PubMed] [PMC]

93.

Wang D, Gu J, Wang T, Ding Z. OncomiRDB: a database for the experimentally verified oncogenic and tumor-suppressive microRNAs. Bioinformatics. 2014;30:2237–8. [DOI] [PubMed]

94.

Ruepp A, Kowarsch A, Schmidl D, Buggenthin F, Brauner B, Dunger I, et al. PhenomiR: a knowledgebase for microRNA expression in diseases and biological processes. Genome Biol. 2010;11:R6. [DOI] [PubMed] [PMC]

95.

Sun X, Dong B, Yin L, Zhang R, Du W, Liu D, et al. PMTED: a plant microRNA target expression database. BMC Bioinformatics. 2013;14:174. [DOI] [PubMed] [PMC]

96.

Jacobs LA, Bewicke-Copley F, Poolman MG, Pink RC, Mulcahy LA, Baker I, et al. Meta-analysis using a novel database, miRStress, reveals miRNAs that are frequently associated with the radiation and hypoxia stress-responses. PLoS One. 2013;8:e80844. [DOI] [PubMed] [PMC]

97.

Chiang K, Shu J, Zempleni J, Cui J. Dietary MicroRNA Database (DMD): an archive database and analytic tool for food-borne microRNAs. PLoS One. 2015;10:e0128089. [DOI] [PubMed] [PMC]

98.

Mooney C, Becker BA, Raoof R, Henshall DC. EpimiRBase: a comprehensive database of microRNA-epilepsy associations. Bioinformatics. 2016;32:1436–8. [DOI] [PubMed]

99.

Hsu PWC, Huang HD, Hsu SD, Lin LZ, Tsou AP, Tseng CP, et al. miRNAMap: genomic maps of microRNA genes and their target genes in mammalian genomes. Nucleic Acids Res. 2006;34:D135–9. [DOI] [PubMed] [PMC]

100.

Hsu SD, Chu CH, Tsou AP, Chen SJ, Chen HC, Hsu PWC, et al. miRNAMap 2.0: genomic maps of microRNAs in metazoan genomes. Nucleic Acids Res. 2008;36:D165–9. [DOI] [PubMed] [PMC]

101.

Betel D, Wilson M, Gabow A, Marks DS, Sander C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 2008;36:D149–53. [DOI] [PubMed] [PMC]

102.

Guo ZW, Xie C, Yang JR, Li JH, Yang JH, Zheng L. MtiBase: a database for decoding microRNA target sites located within CDS and 5’UTR regions from CLIP-Seq and expression profile datasets. Database (Oxford). 2015;2015:bav102. [DOI] [PubMed] [PMC]

103.

Nam S, Kim B, Shin S, Lee S. miRGator: an integrated system for functional annotation of microRNAs. Nucleic Acids Res. 2008;36:D159–64. [DOI] [PubMed] [PMC]

104.

Cho S, Jun Y, Lee S, Choi HS, Jung S, Jang Y, et al. miRGator v2.0: an integrated system for functional investigation of microRNAs. Nucleic Acids Res. 2011;39:D158–62. [DOI] [PubMed] [PMC]

105.

Bhattacharya A, Cui Y. SomamiR 2.0: a database of cancer somatic mutations altering microRNA-ceRNA interactions. Nucleic Acids Res. 2016;44:D1005–10. [DOI] [PubMed] [PMC]

106.

Ruepp A, Kowarsch A, Theis F. PhenomiR: microRNAs in human diseases and biological processes. In: Fan JB, editor. Next-generation microRNA expression profiling technology. Humana Press; 2012. pp. 249–60. [DOI] [PubMed]

107.

Georgakilas G, Vlachos IS, Zagganas K, Vergoulis T, Paraskevopoulou MD, Kanellos I, et al. DIANA-miRGen v3.0: accurate characterization of microRNA promoters and their regulators. Nucleic Acids Res. 2016;44:D190–5. [DOI] [PubMed] [PMC]

108.

Zhang S, Yue Y, Sheng L, Wu Y, Fan G, Li A, et al. PASmiR: a literature-curated database for miRNA molecular regulation in plant response to abiotic stress. BMC Plant Biol. 2013;13:33. [DOI] [PubMed] [PMC]

109.

Paraskevopoulou MD, Vlachos IS, Hatzigeorgiou AG. DIANA-TarBase and DIANA suite tools: studying experimentally supported microRNA targets. Curr Protoc Bioinformatics. 2016;55:12.14.1–18. [DOI] [PubMed]

110.

Jiang Q, Wang Y, Hao Y, Juan L, Teng M, Zhang X, et al. miR2Disease: a manually curated database for microRNA deregulation in human disease. Nucleic Acids Res. 2009;37:D98–104. [DOI] [PubMed] [PMC]

111.

Ritchie W, Flamant S, Rasko JE. mimiRNA: a microRNA expression profiler and classification resource designed to identify functional correlations between microRNAs and their targets. Bioinformatics. 2010;26:223–7. [DOI] [PubMed]

112.

Yang JH, Li JH, Shao P, Zhou H, Chen YQ, Qu LH. starBase: a database for exploring microRNA-mRNA interaction maps from Argonaute CLIP-Seq and Degradome-Seq data. Nucleic Acids Res. 2011;39:D202–9. [DOI] [PubMed] [PMC]

113.

Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014;42:D92–7. [DOI] [PubMed] [PMC]

114.

Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1–12. [DOI] [PubMed]

115.

Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005;102:13944–9. Erratum in: Proc Natl Acad Sci U S A. 2006;103:2464. [DOI] [PubMed] [PMC]

116.

Lujambio A, Lowe SW. The microcosmos of cancer. Nature. 2012;482:347–55. [DOI] [PubMed] [PMC]

117.

Mendell JT. miRiad roles for the miR-17-92 cluster in development and disease. Cell. 2008;133:217–22. [DOI] [PubMed] [PMC]

118.

Gulino R, Forte S, Parenti R, Memeo L, Gulisano M. MicroRNA and pediatric tumors: future perspectives. Acta Histochem. 2015;117:339–54. [DOI] [PubMed]

119.

Zargar S, Tomar V, Shyamsundar V, Vijayalakshmi R, Somasundaram K, Karunagaran D. A feedback loop between microRNA 155 (miR-155), programmed cell death 4, and activation protein 1 modulates the expression of miR-155 and tumorigenesis in tongue cancer. Mol Cell Biol. 2019;39:e00410–18. [DOI] [PubMed] [PMC]

120.

Wang X, Holgado BL, Ramaswamy V, Mack S, Zayne K, Remke M, et al. miR miR on the wall, who’s the most malignant medulloblastoma miR of them all? Neuro Oncol. 2018;20:313–23. [DOI] [PubMed] [PMC]

121.

Zhang Z, Qin YW, Brewer G, Jing Q. MicroRNA degradation and turnover: regulating the regulators. Wiley Interdiscip Rev RNA. 2012;3:593–600. [DOI] [PubMed] [PMC]

122.

Stepanov G, Zhuravlev E, Shender V, Nushtaeva A, Balakhonova E, Mozhaeva E, et al. Nucleotide modifications decrease innate immune response induced by synthetic analogs of snRNAs and snoRNAs. Genes (Basel). 2018;9:531. [DOI] [PubMed] [PMC]

123.

Zhao C, Sun X, Li L. Biogenesis and function of extracellular miRNAs. ExRNA. 2019;1:38. [DOI]

124.

Paliwal SR, Paliwal R, Vyas SP. A review of mechanistic insight and application of pH-sensitive liposomes in drug delivery. Drug Deliv. 2015;22:231–42. [DOI] [PubMed]

125.

Denzler R, McGeary SE, Title AC, Agarwal V, Bartel DP, Stoffel M. Impact of microRNA levels, target-site complementarity, and cooperativity on competing endogenous RNA-regulated gene expression. Mol Cell. 2016;64:565–79. [DOI] [PubMed] [PMC]

126.

Meng Z, Lu M. RNA interference-induced innate immunity, off-target effect, or immune adjuvant? Front Immunol. 2017;8:331. [DOI] [PubMed] [PMC]

127.

Chen Y, Gao DY, Huang L. In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv Drug Deliv Rev. 2015;81:128–41. [DOI] [PubMed] [PMC]

128.

Segal M, Biscans A, Gilles ME, Anastasiadou E, De Luca R, Lim J, et al. Hydrophobically modified let-7b miRNA enhances biodistribution to NSCLC and downregulates HMGA2 in vivo. Mol Ther Nucleic Acids. 2020;19:267–77. [DOI] [PubMed] [PMC]

129.

Lennox KA, Behlke MA. Chemical modification and design of anti-miRNA oligonucleotides. Gene Ther. 2011;18:1111–20. [DOI] [PubMed]

130.

Gasparello J, Manicardi A, Casnati A, Corradini R, Gambari R, Finotti A, et al. Efficient cell penetration and delivery of peptide nucleic acids by an argininocalix[4]arene. Sci Rep. 2019;9:3036. [DOI] [PubMed] [PMC]

131.

Karlsen TA, Brinchmann JE. Liposome delivery of microRNA-145 to mesenchymal stem cells leads to immunological off-target effects mediated by RIG-I. Mol Ther. 2013;21:1169–81. [DOI] [PubMed] [PMC]

132.

Li J, Liang H, Liu J, Wang Z. Poly (amidoamine) (PAMAM) dendrimer mediated delivery of drug and pDNA/siRNA for cancer therapy. Int J Pharm. 2018;546:215–25. [DOI] [PubMed]

133.

Yang H, Qin X, Wang H, Zhao X, Liu Y, Wo HT, et al. An in vivo miRNA delivery system for restoring infarcted myocardium. ACS Nano. 2019;13:9880–94. [DOI] [PubMed] [PMC]

134.

Osborn MF, Khvorova A. Improving siRNA delivery in vivo through lipid conjugation. Nucleic Acid Ther. 2018;28:128–36. [DOI] [PubMed] [PMC]

135.

Daei P, Ramezanpour M, Khanaki K, Tabarzad M, Nikokar I, Hedayati Ch M, et al. Aptamer-based targeted delivery of miRNA let-7d to gastric cancer cells as a novel anti-tumor therapeutic agent. Iran J Pharm Res. 2018;17:1537–49. [PubMed] [PMC]

136.

Li X, Corbett AL, Taatizadeh E, Tasnim N, Little JP, Garnis C, et al. Challenges and opportunities in exosome research–perspectives from biology, engineering, and cancer therapy. APL Bioeng. 2019;3:011503. [DOI] [PubMed] [PMC]

137.

Feng Y, Huang W, Wani M, Yu X, Ashraf M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PloS One. 2014;9:e88685. [DOI] [PubMed] [PMC]

138.

Lundstrom K. Viral vectors in gene therapy. Diseases. 2018;6:42. [DOI] [PubMed] [PMC]

139.

Salah Z, Abd El Azeem EM, Youssef HF, Gamal-Eldeen AM, Farrag AR, El-Meliegy E, et al. Effect of tumor suppressor miR-34a loaded on ZSM-5 nanozeolite in hepatocellular carcinoma: in vitro and in vivo approach. Curr Gene Ther. 2019;19:342–54. [DOI] [PubMed]

140.

Ghasemiyeh P, Mohammadi-Samani S. Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: applications, advantages and disadvantages. Res Pharm Sci. 2018;13:288–303. [DOI] [PubMed] [PMC]

141.

Slack FJ, Chinnaiyan AM. The role of non-coding RNAs in oncology. Cell. 2019;179:1033–55. [DOI] [PubMed] [PMC]

142.

Shete HK, Prabhu RH, Patravale VB. Endosomal escape: a bottleneck in intracellular delivery. J Nanosci Nanotechnol. 2014;14:460–74. [DOI] [PubMed]

143.

Christie RJ, Nishiyama N, Kataoka K. Delivering the code: polyplex carriers for deoxyribonucleic acid and ribonucleic acid interference therapies. Endocrinology. 2010;151:466–73. [DOI] [PubMed]

144.

Linsley CS, Wu BM. Recent advances in light-responsive on-demand drug-delivery systems. Ther Deliv. 2017;8:89–107. [DOI] [PubMed] [PMC]

145.

Bilensoy E. Cationic nanoparticles for cancer therapy. Expert Opin Drug Deliv. 2010;7:795–809. [DOI] [PubMed]

146.

Biscans A, Coles A, Haraszti R, Echeverria D, Hassler M, Osborn M, et al. Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo. Nucleic Acids Res. 2019;47:1082–96. [DOI] [PubMed] [PMC]

147.

Esposito CL, Cerchia L, Catuogno S, De Vita G, Dassie JP, Santamaria G, et al. Multifunctional aptamer-miRNA conjugates for targeted cancer therapy. Mol Ther. 2014;22:1151–63. [DOI] [PubMed] [PMC]

148.

Suter SR, Ball-Jones A, Mumbleau MM, Valenzuela R, Ibarra-Soza J, Owens H, et al. Controlling miRNA-like off-target effects of an siRNA with nucleobase modifications. Org Biomol Chem. 2017;15:10029–36. [DOI] [PubMed] [PMC]

149.

Lai X, Eberhardt M, Schmitz U, Vera J. Systems biology-based investigation of cooperating microRNAs as monotherapy or adjuvant therapy in cancer. Nucleic Acids Res. 2019;47:7753–66. [DOI] [PubMed] [PMC]

150.

Bandi N, Vassella E. miR-34a and miR-15a/16 are co-regulated in non-small cell lung cancer and control cell cycle progression in a synergistic and Rb-dependent manner. Mol Cancer. 2011;10:55. [DOI] [PubMed] [PMC]

151.

Yu HR, Huang LH, Li SC. Roles of microRNA in the immature immune system of neonates. Cancer Lett. 2018;433:99–106. [DOI] [PubMed]

152.

Liu Y, Hardie J, Zhang X, Rotello VM. Effects of engineered nanoparticles on the innate immune system. Semin Immunol. 2017;34:25–32. [DOI] [PubMed] [PMC]

153.

Segal M, Slack FJ. Challenges identifying efficacious miRNA therapeutics for cancer. Expert Opin Drug Discov. 2020;15:987–91. [DOI] [PubMed] [PMC]

154.

Chen PS, Su JL, Cha ST, Tarn WY, Wang MY, Hsu HC, et al. miR-107 promotes tumor progression by targeting the let-7 microRNA in mice and humans. J Clin Invest. 2011;121:3442–55. Erratum in: J Clin Invest. 2017;127:1116. [DOI] [PubMed] [PMC]

155.

Aqeilan RI, Calin GA, Croce CM. miR-15a and miR-16-11 in cancer: discovery, function and future perspectives. Cell Death Differ. 2010;17:215–20. [DOI] [PubMed]

156.

Tang R, Li L, Zhu D, Hou D, Cao T, Gu H, et al. Mouse miRNA-709 directly regulates miRNA-15a/16-1 biogenesis at the posttranscriptional level in the nucleus: evidence for a microRNA hierarchy system. Cell Res. 2012;22:504–15. [DOI] [PubMed] [PMC]

157.

Seven M, Karatas OF, Duz MB, Ozen M. The role of miRNAs in cancer: from pathogenesis to therapeutic implications. Future Oncol. 2014;10:1027–48. [DOI] [PubMed]