Table Of ContentAdvances 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
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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
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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
