REVIEWOpenAccessCircRNAs:biogenesis,functions,androleindrug-resistantTumoursShuoMa1,2,3†,ShanKong1,2,3†,FengWang1*andShaoqingJu1,3*AbstractTargetedtreatment,whichcanspecificallykilltumourcellswithoutaffectingnormalcells,isanewapproachfortumourtherapy.However,tumourcellstendtoacquireresistancetotargeteddrugsduringtreatment.CircularRNAs(circRNAs)aresingle-strandedRNAmoleculeswithuniquestructuresandimportantfunctions.WiththedevelopmentofRNAsequencingtechnology,circRNAshavebeenfoundtobewidespreadintumour-resistantcellsandtoplayimportantregulatoryroles.Inthisreview,wepresentthelatestadvancesincircRNAresearchandsummarizethevariousmechanismsunderlyingtheirregulation.Moreover,wereviewtheroleofcircRNAsinthechemotherapeuticresistanceoftumoursandexploretheclinicalvalueofcircRNAregulationintreatingtumourresistance.Keywords:CircularRNAs(CircRNAs),Tumorresistance,Targetedtreatment,Self-circularize,FunctionsBackgroundCircularRNAs(circRNAs)arenewlyrecognizednon-codingRNAsthatareconsideredsmallendogenousRNAswithawidedistribution,considerablevariety,andmultipleregulatoryfunctions[1].In1976,Sangeretal.discoveredthefirstcircRNAinviroids[2].Sincethen,tensofthousandsofcircRNAshavebeenidentifiedinmultiplecelllinesandspecies[3–5],includingfungi,protozoa,plants,worms,fish,insects,miceandhumans[6–8].CircRNAsareabundant—approximatelyone-eighthofthegenesinthehumantranscriptomecanpro-ducedetectablecircRNAs,andtheexpressionlevelsofthesecircRNAsaremorethantentimesthoseofthecorrespondinglinearmRNAs[9,10].Additionally,cir-cRNAsaremorestablethanlinearRNAsbecauseoftheircovalentclosed-loopstructureandlackoffreeterminalends,whichconfersresistancetodegradationbyribonucleaseR(RNaseR)[11].Moreover,circRNAsareevolutionarilyconserved.Approximately15,000humancircRNAsequencescanbedetectedinmouseorratgenomes[5,12].CircRNAscanalsobeusedtoclas-sifyandidentifydifferenttumourtypesduetotheiradvantageofcelltype-,tissue-,anddevelopmentalstage-specificexpressionandbecausedifferentsubtypesofcir-cRNAscanbeproduc...
