Strategies to Modulate MicroRNA Functions for.pdf

1521-0081/72/3/639667$35.00https:/doi.org/10.1124/pr.119.019026PHARMACOLOGICALREVIEWSPharmacol Rev 72:639667,July 2020Copyright 2020 by The American Society for Pharmacology and Experimental TherapeuticsASSOCIATE EDITOR:ERIC L.BARKERStrategies to Modulate MicroRNA Functions for theTreatment of Cancer or Organ InjuryTae Jin Lee,Xiaoyi Yuan,Keith Kerr,Ji Young Yoo,Dong H.Kim,Balveen Kaur,and Holger K.EltzschigDepartments of Neurosurgery(T.J.L.,K.K.,J.Y.Y.,D.H.K.,B.K.)and Anesthesiology(X.Y.,H.K.E.),McGovern Medical School,University ofTexas Health Science Center at Houston,Houston,TexasAbstract.640Significance Statement.2I.Introduction.640II.Biology,Regulation,and Detection of MicroRNA.641A.Biogenesis and Working Mechanism of MicroRNA.641B.Regulation of MicroRNA Expression.642C.MicroRNA Detection.643III.MicroRNAs in Human Cancers.644A.MicroRNAs as Tumor Suppressors.644B.MicroRNAs as Oncogenes.645C.Circulating MicroRNAs as Biomarkers of Human Cancers.646IV.MicroRNAs in Perioperative Organ Injury.646A.Acute Respiratory Distress Syndrome.646B.Acute Myocardial Infarction.648C.Acute Gut Injury.650V.Pharmacologic Approaches for MicroRNA Modulation.651A.Modification of Nucleotide Analogs to Increase Stability.651B.Viral Delivery of MicroRNAs.652C.Nonviral Delivery of MicroRNAs.6551.Polymers.6562.Lipids.6563.Inorganic Nanoparticles.6564.Exosomes.6565.RNA Nanoparticles.657D.Small Molecule Drugs Targeting MicroRNAs.657VI.MicroRNA Modulation for Disease Therapy.658A.MicroRNA Restoration.658B.MicroRNA Inhibition.659C.Challenges and Limitations.661Address correspondence to:Dr.Xiaoyi Yuan,Department of Anesthesiology,University of Texas Health Science Center at Houston,McGovern Medical School,Houston,TX 77030.E-mail:Xiaoyi.Yuanuth.tmc.edu;or Dr.Tae Jin Lee,Department of Neurosurgery,University of Texas Health Science Center at Houston,McGovern Medical School,Houston,TX 77030.E-mail:Tae.Jin.Leeuth.tmc.eduT.J.L.and X.Y.contributed equally to this work.This work was supported in part by the National Institutes of Health(NIH)National Institute of Diabetes and Digestive and KidneyDiseases(NIDDK)Grants R01-DK097075 and R01-DK109574 and the NIH National Heart,Lung,and Blood Institute(NHLBI)Grants P0I-HL114457,R01-HL109233,R01-HL119837,and R01-HL133900 to H.K.E.;Pilot/Feasibility Program from Texas Medical Center DigestiveDiseases Center through NIH NIDDK Grant P30 DK056338 to T.J.L.;the American Thoracic Society Unrestricted Grant,American HeartAssociation Career Development Award 19CDA34660279,American Lung Association Catalyst Award CA-622265,and The Center forClinical and Translational Sciences,McGovern Medical School Pilot Award 1UL1TR00316701,to X.Y.;American Cancer Society ResearchScholar Grants RSG-19-185-01-MPC to J.Y.Y.;NIH National Cancer Institute(NCI)Grant R01 CA150153 and P01 CA163205 and NIHNational Institute of Neurologic Disorders and Stroke(NINDS)Grant R01 NS064607 to B.K.;and NIH NINDS Grant R01 NS104280 toD.H.K.https:/doi.org/10.1124/pr.119.019026.639at East Carolina Univ on June 18,2020Downloaded from VII.Perspectives.661Acknowledgments.662References.662AbstractCancer and organ injurysuch as thatoccurring in the perioperative period,including acutelunginjury,myocardialinfarction,andacutegutinjuryare among the leading causes of death in the UnitedStatesandimposeasignificantimpactonqualityoflife.MicroRNAs(miRNAs)have been studied extensivelyduring the last two decades for their role as regulatorsof gene expression,their translational application asdiagnostic markers,and their potential as therapeutictargets for disease treatment.Despite promising preclinicaloutcomes implicating miRNA targets in disease treatment,only a few miRNAs have reached clinical trials.This likelyrelatestodifficultiesinthedeliveryofmiRNAdrugstotheirtargets to achieve efficient inhibition or overexpression.Therefore,understandinghowtoefficientlydelivermiRNAsinto diseased tissues and specific cell types in patientsis critical.This review summarizes current knowledgeon various approaches to deliver therapeutic miRNAsor miRNA inhibitors and highlights current progress inmiRNA-based disease therapy that has reached clinicaltrials.Based on ongoing advances in miRNA delivery,we believe that additional therapeutic approaches tomodulate miRNA function will soon enter routinemedical treatment of human disease,particularly forcancer or perioperative organ injury.SignificanceStatementMicroRNAshavebeenstudied extensively during thelast two decades in cancerandorganinjury,includingacutelunginjury,myocardialinfarction,andacutegutinjury,fortheirregulationofgeneexpression,application as diagnostic markers,and thera-peutic potentials.In this review,we specifically emphasizethe pros and cons of different delivery approaches tomodulate microRNAs,as well as the most recent excit-ing progress in the field of therapeutic targeting ofmicroRNAs for disease treatment in patients.I.IntroductionConsidered together,cancer and perioperative organinjury are among the leading causes of death in Westerncountries.According to the Center for Disease Controland Preventions National Vital Statistics,cancer aloneaccounts for 21%of deaths and is the second leadingcause of mortality in the United States.Coupled withthe economic burden of care,which is predicted toincrease to 173 billion dollars by 2020,cancer poses asignificant impact on society(Mariotto et al.,2011).Theidentification of therapeutic targets for cancer treatmenthas been an area of intense research for several decades.Advancements in cancer immunotherapy have improvedoutcomes for certain subsets,such as melanoma,bladdercancer,kidney cancer,and non-Hodgkin lymphoma.However,there is still an urgent need for the develop-ment of new therapeutic targets for cancer treatment.Perioperative organ injury,including acute respiratorydistress syndrome(ARDS),myocardial infarction,andacute gut injury,account for the third leading cause ofdeath in the United States if considered as a separatecatalog(Bartels et al.,2013).For instance,ARDS aloneaccountsformore thananestimated200,000deaths peryear in the United States when extrapolated from the2017AmericanHeartAssociationAnnualSurvey(Bellaniet al.,2016).Thus,the development of novel therapeuticmeasures to prevent or treat perioperative organ injury isimperative to reduce mortality rates during the peri-operative period.In both cases,cancer and perioperative organ injuryare often the results of dysregulation of genetic in-formation as a response to environmental changes.Inthe last 2 decades,accumulating evidence has indicatedthat genetic and epigenetic alterations are not limitedto protein-coding genes.Rather,noncoding RNAs,in-cluding microRNAs(miRNAs),have risen as a majorplayer in mediating the regulation of gene expressionABBREVIATIONS:AAV,adeno-associated virus;AGI,acute gut injury;ALI,acute lung injury;AMI,acute myocardial infarction;AML,acute myeloid leukemia;AMO,antisense modified oligonucleotide;ARDS,acute respiratory distress syndrome;AT-RvD1,aspirin-triggeredresolvin D1;BCL-2,B-cell lymphoma 2;CDK6,cyclin-dependent kinase 6;CLL,chronic lymphocytic leukemia;c-Met,cellular mesenchymalepithelial transition factor;c-Myc,cellular myelocytomatosis;CPC,cardiac progenitor cell;CpG,59-C-phosphate-G-39;CRC,colorectal cancer;CSC,cancer stem cell;DLBCL,diffuse large b-cell lymphoma;DNMT,DNA methyltransferase;DOPC,1,2-dioleoyl-sn-glycero-3-phosphocholine;DSS,dextran sodium sodium;E2F,E2F transcription factor;EGFR,epidermal growth factor receptor;EV,extracellularvesicle;29-F,29-fluoro;FA,folate;FDA,Food and Drug Administration;HCC,hepatocellular carcinoma;HCV,hepatitis C virus;HIF,hypoxia-inducible factor;HIV,human immunodeficiency virus;IBD,inflammatory bowel disease;IL,interleukin;Let-7,Lethal-7;lin-14,abnormal cellLINeage-14;LNA,locked nucleic acid;LNP,lipid nanoparticle;LPS,lipopolysaccharide;MCL-1,myeloid cell leukemia 1;MI,myocardialinfarction;miR,microRNA;miRNA,microRNA;MVB,multivesicular body;ncRNA,noncoding RNA;NLRP3,NLR family pyrin domaincontaining 3;NPRM,nano-proresolving medicine;NSCLC,nonsmall-cell lung cancer;onco-miR,oncogenic miRNA;PARP-1,poly(ADP-ribose)polymerase 1;PEI,polyethyleneimine;PLGA,poly lactic-co-glycolic acid;PMN,polymorphonuclear neutrophil;PNA,peptide bondbasednucleic acid;pre-miR,precursor-miRNA;pri-miRNA,primary-miRNA;PS,phosphorothioate;qRT-PCR,quantitative real-time polymerasechain reaction;Ras,rat sarcoma;RISC,RNA-induced silencing complex;RNAi,RNA interference;RvD1,resolvin D1;SEB,Staphylococcalenterotoxin B;siRNA,short interfering RNA;SNP,single polymorphism;SOCS-1,suppressor of cytokine signaling;Sp1,specificity protein 1;SVP,saphenous veinderived pericyte progenitor cell;Th,T helper;TNBC,triple-negative breast cancer;Treg,regulatory T cell;39 UTR,39 untranslated region;VILI,ventilator-induced lung injury;3WJ,three-way junction;XPO5,Exportin-5.640Lee et al.into biologic phenotypes together with proteins.Noncod-ing RNAs(ncRNAs)are endogenously transcribed intofunctional RNA species but are not translated further intoproteins,astheylackanopenreadingframewithstartandstop codons.Although they are not used as templates forproteinsynthesis,ncRNAshavebeenfoundtoplaydiversefunctional roles in many biologic processes and diseasedevelopment(Cech and Steitz,2014).In general,ncRNAscan be divided intotwo groups based on the length of theirfinal product.RNAs longer than 200 nucleotides are longnoncoding RNAs,whereas RNAs that are shorter than200 nucleotides are referred to as short noncoding RNAs.Approximately 22 nucleotides in length,miRNAs arethe smallest members of ncRNAs,and they are highlyconserved evolutionarily(Bartel,2009).Since the dis-covery of abnormal cell LINeage-14(lin-14)from Cae-norhabditis elegans in 1993,miRNAs have been themostheavily studiedamongshortnoncoding RNAs(Leeet al.,1993;Wightman et al.,1993)and have beenidentifiedinnearlyeveryeukaryote,includinginhumans.Both studies during this time found that a small pieceof RNA transcribed from the lin-4 gene regulates theexpression of genes through sequence-specific binding.However,its impact on medical science has only beenappreciated in the last 20 years,since the discovery ofpost-transcriptional gene silencing activity by short in-terfering RNAs(siRNAs)in plants in 1999(Hamilton andBaulcombe,1999).In 2001,RNA interference(RNAi)wasalso demonstrated in mammalian cells with syntheticartificial siRNAs(Elbashir et al.,2001).According tomiRBase(http:/www.mirbase.org/),there are approxi-mately2588miRNAsinhumans,andthenumberisstillgrowing as new miRNAs are discovered.It has beenestimatedthatmorethan60%ofhumangenes,involvedin various biologic processes,are regulated by miRNAs(Bartel,2009),such as during the cell cycle(Hatfieldet al.,2005),differentiation and development(Chenet al.,2004),and metabolism(Boehm and Slack,2006).miRNAs are also involved in the oncogenesis,progres-sion,and metastasis phases of multiple types of cancer(Calin and Croce,2006).Besides,many miRNAs havebeen identified as major regulators during the patho-genesis of perioperative organ injury,cardiovasculardisease,inflammation,sepsis,anesthetic neurotoxicity,andinfectiousdiseases,inwhichmiRNAexpressionlevelsmay play a role as useful perioperative biomarkers andpharmacologic targets(Neudecker et al.,2016).Interest-ingly,the same miRNAs of pathologic importance incertain chronic and inflammatory diseases seem to playsimilar functions in both cancer and perioperative organinjury.For example,miR-155,one of the most extensivelystudied oncogenic miRNAs in various types of cancer,isfound to be overexpressed in human carotid plaques andpromotes the proinflammatory activity of macrophagesto exaggerate arteriosclerosis in cardiovascular diseases(Nazari-Jahantigh et al.,2012).A substantial body ofevidence shows that each disease displays a uniqueprofile of miRNA expression,which is distinct frommiRNA expression in disease-free,normal tissue.Thesedifferentially regulated miRNAs are called“signaturemiRNAs.”Signature miRNAs are believed to serve asdiagnostic or prognostic markers,which may improvethe conventional detection methods currently in use.Inaddition,some,if not all,of the signature miRNAs mayserve as useful therapeutic targets in the developmentof antidisease strategies.This review intends to de-scribe the current knowledge of miRNAs in varioushuman diseases by highlighting the most recent studieson perioperative organ injury and cancer.In addition,itwillfocusonnovelapproachestoaltermiRNAfunctioninhuman diseasean approach that has unequivocallyimportant translational implications.II.Biology,Regulation,and Detectionof MicroRNAA.Biogenesis and Working Mechanism of MicroRNAApproximately 70%of miRNA coding genes are associ-atedwithprotein-codinghostgenesandarecotranscribed.Only 30%of miRNAs are transcribed from their ownopen reading frames located in intergenic areas(Bartel,2009,2018;Ha and Kim,2014).In either case,duringthe expression process,miRNA coding sequences arefirsttranscribedbyRNApolymeraseIIintoalongprimarytranscript of up to 10 kb,called primary-miRNA(pri-miRNA)(Lee et al.,2004)(Fig.1).The pri-miRNAtranscript is then processed by a nuclear RNase III calledDroshaintoashorterlengthoftranscript(about70bases),forming a hairpin-like structure,called precursor-miRNA(pre-miR)(Lee et al.,2003).The processed pre-miR isexported to the cytoplasm through nuclear membranechannel protein Exportin-5(XPO5)(Yi et al.,2003).Arecent study showed that XPO5 activity can be regulatedby pre-miR phosphorylation.The phosphorylation byextracellular signal-regulated kinase suppresses the pre-miR export through XPO5 in cancers(Sun et al.,2016).Once translocated into the cytoplasm,the terminalhairpin loop of the pre-miR is further cleaved by Dicer,acytoplasmic RNase III,to produce a 22-nucleotidelongmature miRNA(Hutvgner et al.,2001).Interestingly,itwas suggested that intact RNAi machinery is critical tomaintaining stem cell populations during early develop-ment.Studies in which Dicer was lost had a lethal effect,showing stem cell depletion in embryos during the earlydevelopmental stages of mice(Bernstein et al.,2003).The mature miRNA binds to Argonaute 2 andtransactivation-responsive RNA-binding protein toform the RNA-induced silencing complex(RISC)(Redfernet al.,2013).Although associated with RISC,inactivestrands,mostly 39 end,are degraded,leaving the otheractive strand with the RISC until guided to the 39 un-translated region(39 UTR)of target mRNAs(Ha and Kim,2014).siRNAisalsoprocessed,inasimilarwaytomiRNAs,toadouble-strandedRNAbyDicerandloadedontoRISCtoMiRNA Delivery for Treatment of Cancer or Organ Injury641bind to its target mRNA.The binding between the targetmRNAandsiRNAisfullycomplementary(CarthewandSontheimer,2009).Unlike the working mechanism ofsiRNA,miRNAs recognize their target mRNAs throughpartial complementary sequences between the secondandtheeighthnucleotide,called“seedsequences.”Oncethe seed sequence region of miRNA forms the partialbase pairin