Advances in Experimental Medicine and Biology 1385 Ulf Schmitz Olaf Wolkenhauer Julio Vera-González Editors Systems Biology of MicroRNAs in Cancer Advances in Experimental Medicine and Biology Volume 1385 SeriesEditors Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRSandUniversityofBordeaux,PessacCedex,France HaidongDong,DepartmentsofUrologyandImmunology,MayoClinic,Rochester, MN,USA HeinfriedH.Radeke,InstituteofPharmacology&Toxicology,ClinicoftheGoethe UniversityFrankfurtMain,FrankfurtamMain,Hessen,Germany NimaRezaei,ResearchCenterforImmunodeficiencies,Children’sMedicalCenter, TehranUniversityofMedicalSciences,Tehran,Iran OrtrudSteinlein,InstituteofHumanGenetics,LMUUniversityHospital,Munich, Germany JunjieXiao,CardiacRegenerationandAgeingLab,InstituteofCardiovascular Sciences,SchoolofLifeScience,ShanghaiUniversity,Shanghai,China Advances in Experimental Medicine and Biology provides a platform for scientific contributions in the main disciplines of the biomedicine and the life sciences. This series publishes thematic volumesoncontemporaryresearchintheareas ofmicro- biology,immunology,neurosciences,biochemistry,biomedicalengineering,genet- ics, physiology, and cancer research. Covering emerging topics and techniques in basicandclinicalscience,itbringstogethercliniciansandresearchersfromvarious fields. AdvancesinExperimentalMedicineandBiologyhasbeenpublishingexceptional worksinthefieldforover40years,andisindexedinSCOPUS,Medline(PubMed), EMBASE, BIOSIS, Reaxys, EMBiology, the Chemical Abstracts Service (CAS), andPathwayStudio. 2021ImpactFactor:3.650(nolongerindexedinSCIEasof2022) (cid:129) (cid:129) Ulf Schmitz Olaf Wolkenhauer á Julio Vera-Gonz lez Editors Systems Biology of MicroRNAs in Cancer Editors UlfSchmitz OlafWolkenhauer DepartmentofMolecularandCell DepartmentofSystemsBiologyand Biology,CentreforTropical Bioinformatics BioinformaticsandMolecularBiology UniversityofRostock JamesCookUniversity Rostock,Germany Townsville,QLD,Australia JulioVera-González DepartmentofDermatology Friedrich-Alexander-UniversitätErlangen- NürnbergandUniversityHospital Erlangen Erlangen,Bayern,Germany ISSN0065-2598 ISSN2214-8019 (electronic) AdvancesinExperimentalMedicineandBiology ISBN978-3-031-08355-6 ISBN978-3-031-08356-3 (eBook) https://doi.org/10.1007/978-3-031-08356-3 ©TheEditor(s)(ifapplicable)andTheAuthor(s),underexclusivelicensetoSpringerNatureSwitzerland AG2022 Thisworkissubjecttocopyright.AllrightsaresolelyandexclusivelylicensedbythePublisher,whether thewholeorpartofthematerialisconcerned,specificallytherightsoftranslation,reprinting,reuseof illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similarordissimilarmethodologynowknownorhereafterdeveloped. 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ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland Contents 1 TheRoleofMicroRNAsinCancerBiologyandTherapy fromaSystemsBiologyPerspective. .. . . .. . . . .. . . .. . . . .. . . .. 1 XinLai,UlfSchmitz,andJulioVera 2 CirculatingMicroRNAsasCancerBiomarkersinLiquid Biopsies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 BeatrizSuárez,CarlaSolé,MaitaneMárquez,FrancescaNanetti, andCharlesHendersonLawrie 3 RegulationofImmuneCellsbymicroRNAsandmicroRNA-Based CancerImmunotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 RafaelaNasserVeiga,ÉrikaPereiraZambalde,LiviaCox, TayanaShultzJucoski,AnaFláviaKohler, TamyresMingoranceCarvalho,AnaCarolinaRodrigues, BeatrizLudwig,KaitlynCrowley,JaquelineCarvalhodeOliveira, andMariaAngelicaCortez 4 MachineLearningBasedMethodsandBestPractices ofmicroRNA-TargetPredictionandValidation. . . . . . . . . . . . . . . 109 NeetikaNathandStefanSimm 5 TurningDatatoKnowledge:OnlineTools,Databases, andResourcesinmicroRNAResearch. . . . . . . . . . . . . . . . . . . . . . 133 IdoBlass,KerenZohar,andMichalLinial 6 BioinformaticsMethodsforModelingmicroRNARegulatory NetworksinCancer.. . . . .. . . . .. . . . .. . . . .. . . . .. . . . .. . . . .. 161 TaoPan,YueyingGao,GangXu,andYongshengLi 7 Analysisofthep53/microRNANetworkinCancer. . . . . . . . . . . . . 187 MarkusKaller,SabineHünten,HelgeSiemens,andHeikoHermeking v vi Contents 8 MachineLearningUsingGene-SetstoInfermiRNAFunction. . . . 229 AndrewDhawanandFrancescaM.Buffa 9 miRNA:miRNAInteractions:ANovelModeofmiRNA RegulationandItsEffectOnDisease.. . . .. . . . .. . . .. . . . .. . . .. 241 MeredithHillandNhamTran 10 ClustMMRAv2:AScalableComputationalPipelineforthe IdentificationofMicroRNAClustersActingCooperatively onTumorMolecularSubgroups. . . . . . . . . . . . . . . . . . . . . . . . . . . 259 CélineHernandez,GabrieleCancila,OlivierAyrault, AndreiZinovyev,andLoredanaMartignetti 11 3DModelingofNon-codingRNAInteractions. . . . . . . . . . . . . . . . 281 KrishnaPalSinghandShailendraGupta About the Editors Ulf Schmitz’s research focus is on RNA biology and systems medicine. He inte- grates in silico, in vitro, and in vivo approaches in advanced interdisciplinary research. His team develops integrative systems medicine workflows along with tools and databases to identify and study interactions between RNAs and other molecules,mechanismsofgeneregulation,andgeneregulatorynetworks. With the goal of achieving a deeper understanding of processes involved in disease emergence and progression, his projects focus on different cancer entities and possible avenues for therapeutic interventions and optimized treatment schedules. OlafWolkenhauer’s researchcombinesdata-drivenmodellingwithmodel-driven experimentation, using a wide range of approaches, including machine learning, statistics, systems theory, and stochastic processes. He has extensive experience in developingsystemstheoreticconceptsanddevelopingalgorithms,workflows,stan- dards,andsoftwaretoolsthatsupporttheanalysisdatawithapplicationsinbiomed- icine.Hisspecificinterestisinunderstandingthefunctioningofcellswithinatissue andhowsuchwhole-partrelationshipscanbeusedtoidentifyprinciplesunderlying tissue(mal)functioning. JulioVera-González isaphysicistworkinginmedicalsystemsbiologysince2005. Hisexpertiseisinmathematicalmodelling,bioinformatics,andnetworkbiology.He appliesmulti-criteriadecisionalgorithmstopatientclassificationandtherapyassess- ment.Hisprimaryinterestistheroleof(non-coding)RNAregulationintheinterplay betweencancerandtheimmunesystem,aswellasitsimpacton(immuno)therapy. vii Chapter 1 The Role of MicroRNAs in Cancer Biology and Therapy from a Systems Biology Perspective XinLai,UlfSchmitz,andJulioVera Abstract SincethediscoveryofmicroRNAs(miRNAs)inCaenorhabditiselegans, ourunderstandingoftheircellularfunctionhasprogressedcontinuously.Today,we haveagoodunderstandingofmiRNA-mediatedgeneregulation,miRNA-mediated cross talk between genes including competing endogenous RNAs, and miRNA- mediatedsignalingtransductionbothinnormalhumanphysiologyandindiseases. Besides,thesenoncodingRNAshaveshowntheirvalueforclinicalapplications, especially in an oncological context. They can be used as reliable biomarkers for cancer diagnosis and prognosis and attract increasing attention as potential thera- peutic targets. Many achievements made in the miRNA field are based on joint efforts from computational and molecular biologists. Systems biology approaches, whichintegratecomputationalandexperimentalmethods,haveplayedafundamen- talroleinuncoveringthecellularfunctionsofmiRNAs. In this chapter, we review and discuss the role of miRNAs in oncology from a systembiologyperspective.WefirstdescribebiologicalfactsaboutmiRNAgenetics andfunction.Next,wediscusstheroleofmiRNAsincancerprogressionandreview theapplicationofmiRNAsincancerdiagnosticsandtherapy.Finally,weelaborate on the role that miRNAs play in cancer gene regulatory networks. Taken together, weemphasizetheimportanceofsystemsbiologyapproachesinourcontinuedefforts tostudymiRNAcancerregulation. Authorcontribution:Conceptualization:XL,US,JV;Visualization:XL;Writing-originaldraft: XL,JV;Writing-reviewandediting:XL,US,JV. X.Lai(*)·J.Vera(*) LaboratoryofSystemsTumorImmunology,DepartmentofDermatology,Friedrich-Alexander- UniversitätErlangen-Nürnberg(FAU)andUniversitätsklinikumErlangen,Erlangen,Germany DeutschesZentrumImmuntherapieandComprehensiveCancerCenterErlangen-EMN, Erlangen,Germany e-mail:[email protected];[email protected] U.Schmitz DepartmentofMolecularandCellBiology,CollegeofPublicHealth,MedicalandVeterinary Sciences,JamesCookUniversity,Townsville,QLD,Australia ©TheAuthor(s),underexclusivelicensetoSpringerNatureSwitzerlandAG2022 1 U.Schmitzetal.(eds.),SystemsBiologyofMicroRNAsinCancer,Advancesin ExperimentalMedicineandBiology1385, https://doi.org/10.1007/978-3-031-08356-3_1 2 X.Laietal. Keywords mRNAdestabilization·Translationrepression·Mathematical modelling·Networkbiology·Bioinformatics·Posttranscriptionalgeneregulation· Oncomir·TumorsuppressormiRNA·Metastamir·CirculatingmiRNA 1.1 BiologicalFactsAboutmiRNABiogenesisandFunction MicroRNAs (miRNAs) are a class of small endogenous noncoding RNAs with a lengthofaround22nucleotides(nt).miRNAsareevolutionarilyconservedregula- torymoleculesthat,inmostcases,modulatethestabilityand/ortranslationoftarget mRNAsthroughdirectbindingtothetarget’s30 UTR(Bartel2004).miRNAswere firstfoundtobepivotalforCaenorhabditiselegansdevelopment(Vellaetal.2004) anditwassoondemonstratedthattheyplayakeyroleingeneexpressionregulation in both animals and plants. More recently, there is mounting evidence suggesting that miRNAs and other similar noncoding RNAs are also important in viral and bacterial gene regulation, as well as in the microbe-mediated host gene regulation. Taken together, miRNAs are ubiquitous posttranscriptional regulators of gene expression and important in normal cell physiology and function (Cardin and Borchert2017). Todateover2500miRNAsequenceshavebeenidentifiedinthehumangenome andregisteredinthemiRBasedatabase(Kozomaraetal.2019).ThesemiRNAsare estimated to regulate more than half of all protein-coding genes (Friedman et al. 2009).Thisindicatestheirpervasiverolesintheregulationofcellularprocesses,like proliferation,differentiation,andapoptosis.Inadditiontoexertingcriticalfunctions during normal development and cellular homeostasis, miRNA dysregulation has beenfoundinmanyhumandiseases,likecancer(HwangandMendell2006).Thus, understanding the function of miRNAs in gene regulation is crucial for unraveling mechanismsunderlyinghumanpathogenesisandimprovingtherapeuticapproaches inhumandiseases. 1.1.1 miRNA Biogenesis The miRNA biogenesis pathway is a complex process composed of multiple steps (Fig. 1.1) (Berezikov 2011; Filipowicz et al. 2008; Krol et al. 2010). At first, long primary transcripts known as primary miRNAs (pri-miRNAs) aretranscribedfrom miRNA genes by RNA polymerase II (Pol II). Pri-miRNA molecules have a 5- 0-terminal 7-methylguanosine (m7G) cap, which is extended by a hairpin structure withaterminalloopanda~32ntlongimperfectlybase-pairedstemandendwitha30 poly(A)tail.DependingonthefeaturesofmiRNAgenes,pri-miRNAscancontain singleormultiplemiRNApairsthatformhairpinstructures.Next,withthehelpof thecomplexthatincludesDroshaanditsbindingpartnerDGCR8,pri-miRNAsare