Revisiting cancer hallmarks: insights from the interplay ...

Elevated ROS levels, due to imbalance of ROS generation or elimination, is termed oxidative stress and is one of the hallmarks of cancer. Skiptomaincontent Advertisement SearchSpringerLink Search Revisitingcancerhallmarks:insightsfromtheinterplaybetweenoxidativestressandnon-codingRNAs DownloadPDF DownloadPDF AbstractCancerisoneofthemostcommondiseaseworldwide,withcomplexchangesandcertaintraitswhichhavebeendescribedas“TheHallmarksofCancer.”Despiteincreasingstudiesonin-depthinvestigationofthesehallmarks,themolecularmechanismsassociatedwithtumorigenesishavestillnotyetbeenfullydefined.Recently,accumulatingevidencesupportstheobservationthatmicroRNAsandlongnoncodingRNAs(lncRNAs),twomainclassesofnoncodingRNAs(ncRNAs),regulatemostcancerhallmarksthroughtheirbindingwithDNA,RNAorproteins,orencodingsmallpeptides.Reactiveoxygenspecies(ROS),thebyproductsgeneratedduringmetabolicprocesses,areknowntoregulateeverystepoftumorigenesisbyactingassecondmessengersincancercells.ThedisturbanceinROShomeostasisleadstoaspecificpathologicalstatetermed“oxidativestress”,whichplaysessentialrolesinregulationofcancerprogression.Inaddition,theinterplaybetweenoxidativestressandncRNAsisfoundtoregulatetheexpressionofmultiplegenesandtheactivationofseveralsignalingpathwaysinvolvedincancerhallmarks,revealingapotentialmechanisticrelationshipinvolvingncRNAs,oxidativestressandcancer.Inthisreview,weprovideevidencethatshowstheessentialroleofncRNAsandtheinterplaybetweenoxidativestressandncRNAsinregulatingcancerhallmarks,whichmayexpandourunderstandingofncRNAsinthecancerdevelopmentfromthenewperspective. IntroductionCancerinitiationandprogressionarecausedbyalterationsinkeyprocesses,whichallowcancercellstoacquirespecificcharacteristicssummarizedbyHanahanandWeinbergas“TheHallmarksofCancer”[1].Theyhaveproposedeighthallmarks(sustainingproliferativesignaling,evadinggrowthsuppressors,activatinginvasionandmetastasis,enablingreplicativeimmortality,inducingangiogenesis,resistingcelldeath,reprogrammingenergymetabolism,andavoidingimmunedestruction)andtwoenablingcharacteristics(genomeinstabilityandmutationandtumor-promotinginflammation)inwhichsuccessivealterationsaccumulateinmultipleprotein-codingandnoncodinggenes.Indeed,protein-codinggenesplaycentralrolesinregulationcancerprogression,andmanystudieshavebeenconductedtoexplorethepotentialmechanisms[2,3,4,5].However,large-scalegenomesequencinghasrevealedthatmorethan90%ofthehumangenomeisactivelytranscribed,butlessthan2%ofthetotalgenomeencodesproteins.Thus,non-codingRNAs(ncRNAs)aremajorcomponentofthehumantranscriptomeandaffectnormalexpressionofthegenes,includingoncogenesandtumorsuppressivegenes,whichmakethemanewclassoftargetsfordrugdiscoveryincancer.Reactiveoxygenspecies(ROS)aregenerallydefinedasoxygen-containingfreeradicalswithhighlyreactivepropertiessuchashydroxylfreeradicals(HO•)andsuperoxide(O2•−)andnon-radicalssuchashydrogenperoxide(H2O2)[6].ConventionaldoctrinesuggestedthatROSwereonlymetabolicwaste,whichwereharmfultonucleicacids,lipids,andproteins[7].Infact,ROSplaydualrolesinbiologicaleventsaccordingtotheircellularlevel.LowormoderateconcentrationofROSactasimportantsecondmessengerstoregulatemultifarioussignalingpathwaysinvolvedincellproliferation,apoptosis,migration,DNAdamage,differentiationandchemoresistance[8].Incontrast,highconcentrationofROScausedamagetocellularmacromoleculessuchasDNA,lipid,andproteins,whichleadstoinductionofapoptosis[9].Indeed,ROSlevelsarebalancedviaseveraldetoxificationprocessesregulatedbyantioxidantenzymes,whichistermed“RedoxHomeostasis”[10].Thedisruptionofredoxhomeostasisisknownas“oxidativestress”,whichdriveskeycellularphysiologicalregulatoryresponsesandleadstodiversepathologicalconditions[11].Cancercellsareusuallyinachronicstateofoxidativestress,asevidencedbyelevatedROSlevelsandaccompanieddown-regulationofcellularantioxidantsystems[12].Thisformofphysiologicaloxidativestress(eustress)endowcancercellswithasustainedproliferativeandaggressivephenotypetopromotemalignanttransformation,whereasexcessiveoxidativeburden(distress)causedamagetocellularmacromoleculesandaretoxictocancercells[11].Itisthereforeimportanttoinvestigatethedetailedmechanismsunderlyingoxidativestress-inducedcancerprogressionforbettercancermanagement.Inthisreview,weintroducerecentadvancesintheunderstandingofncRNAsinvolvedincancerhallmarks,particularlyfocusingontheirinterplaywithROS,whichwillcontributetoabetterunderstandingofcancerprogressionandmaybenefitthedevelopmentofnovelstrategiesforcancertreatment.GeneralcharacterizationandfunctionsofncRNAENCODEindicatesthat,althoughmuchofthehumangenomeistranscribedintoRNAs,themajorityofthesedonotcodeforproteins[13].ThesencRNAsaregroupedintotwomajorclassesbasedonthetranscriptsize:smallncRNAsandlongncRNAs(lncRNAs)(Table 1)[14].ThesizeofsmallncRNAisusuallylessthan200nucleotides(nt).ThesearedividedintomicroRNA(miRNA),PIWI-interactingRNA(piRNA),smallnucleolarRNA(snoRNA),smallnuclearRNA(snRNA),smallinterferingRNA(siRNA),andthenewclassoftRNA-derivedfragments(tRF)[15,16].miRNAisaclassofsmallnon-codingRNAwhoselengthisabout19–24 nt.TheyregulategeneexpressionprocessesbybindingtomiRNAresponseelements(MREs)inRNAsequencesandinhibitingsubsequenttranslationbyinducingdegradationoftargetRNAtranscripts[17].piRNAsaresmallRNAs24–32 ntinlengthwhicharederivedfromrepeatedsequenceswithinthegenome.TheyareidentifiedasendogenoussiRNAsandregulategermcelldevelopment,stemcellself-renewalandthesilencingoftransposons[18].ThesnoRNAscompriseaclassofnucleolus-enrichedncRNAswithconservedstemmotifsthatactasguidestoinducechemicalmodificationandmaturationofothernon-codingRNA,suchasrRNA[19].snoRNAsarealsofurtherprocessedintomiRNAsthattargetcellularmRNAs.ThetRNA-derivedfragmentsareanumberofsequencingreadswhichmaptoRNAfragmentsderivedfromthecleavageoftRNAtranscripts,andhavepotentialimplicationingenesuppressionaswellasmanyothercellfunctionswhicharesummarizedinthesereviews[20,21]. Table1GeneralcharacterizationandfunctionofmainncRNAsFullsizetableIncontrast,longncRNAisusuallymorethan200 ntlengthandisclassifiedintodifferentcategoriesaccordingtotheirlocalizationingenome,modesofaction,andfunction[22].Onthebasisoftheirlocalizationingenome,lncRNAsaredividedinto:introniclncRNAsgeneratedfromtheregioninintronsofprotein-codinggenes;intergeniclncRNAs(lincRNA)generatedfromtheregionbetweentwoprotein-codinggenes;enhancerlncRNAs(elncRNA)generatedfromtheregionsinenhancer;bidirectionallncRNAsgeneratedfromtheregioninthevicinityofacodingtranscriptoftheoppositestrand;sense-overlappinglncRNAsoverlappedwithseveralintronsandexonsofdiveseprotein-codinggenesinDNAsensestrand;antisensetranscriptsgeneratedfromtheDNAantisensestrand[23].Accordingtotheirdiversefunctions,lncRNAsareclassifiedassignaling,decoy,guide,andscaffoldlncRNAs[24].SignalinglncRNAsareinvolvedinspecificsignalingpathwaysandtheirexpressionpresentsanactivesignalingevent,witheitherdirectorindirectroles.DecoylncRNAsregulategeneexpressionbyservingasadecoytopreventaccessoftranscriptionfactorstochromatinortocompetitivelybindtomiRNA.Forexample,lncRNAGAS5(growtharrestspecific5)wasfoundtodirectlyinteractwiththeWWdomainofYAPtofacilitatetranslocationofendogenousYAPfromthenucleustothecytoplasm,thuspromotingphosphorylationandsubsequentlyubiquitin-mediateddegradationofYAPtoinhibitcolorectalcancer(CRC)progressioninvitroandinvivo[25].GuidelncRNAsbindtotheregulatoryorenzymaticallyactiveproteincomplexesandrecruitthemtotargetgenes.Forinstance,thep53-regulatedlongnoncodingRNAlincRNA-p21hasbeenreportedtoactinconcertwithhnRNP-Kasacoactivatorforp53-dependentp21transcription,thuspromotingPolycombtargetgeneexpressionandenforcingtheG1/Scheckpoint[26].ScaffoldlncRNAsfunctionasscaffoldstoformvariousproteincomplexes,whichaffectgeneexpressionandchromosomaldynamics.Forexample,metastasisassociatedwithlungadenocarcinomatranscript-1(MALAT1),afunctionallongnon-codingRNAhighlyexpressedincolorectalcancercells,promotescellproliferationandmigrationbybindingtoSFPQ,thusreleasingPTBP2fromtheSFPQ/PTBP2complex[27].InadditiontotheselinearncRNAs,anewtypeofcircularncRNA(circRNA)hasrecentlybeenidentified.ThestructureofcircRNAsdiffersfromotherlinearlncRNAsinwhichtheir3′and5′endsarenotfreebutcovalentlyjoined.CircRNAsaremainlyarisedfromtheexonsofprotein-codinggenes,aswellastheintronic,intergenic,UTR-regions,ncRNAlociandlocationsantisensetoknowntranscripts[28,29].Becauseoftheirdistinctstructure,circRNAsareresistanttonucleasesandhavearelativelylonghalf-life,makingthemrelativelyeasytodetectintissues,serum,andurineaspotentialbiomarkersforhumancancer[24].Indeed,circRNAsareimplicatedinavarietyofcancers(includinggastriccancer,hepatocellularcancer,bladdercancer,andesophagealcancer,andothers)byactingascompetitiveendogenousRNAs(ceRNAs),whichregulategeneexpressionviathecompetitivebindingofmiRNA.AnexampleofthisisciRS-7,whichactsasaspongeformiR-7topromotecolorectalcancerprogressionbyreleasingtherepressionofoncogenessuchasYY1bytumorsuppressormiR-7[30].Insummary,ncRNAs,particularlymiRNAsandlncRNAs,areemergingasanovelclassofregulatorsassociatedwithmodulationofcellularbiologicalprocessesandarecloselyrelatedtotumorigenesis,whichallowsthemtoserveaspotentialdiagnosisandprognosisbiomarkersforcancertherapy.OxidativestressincancerprogressionROSarebroadlydefinedasoxygen-containingspecieswithreactiveproperties,includinghydroxylfreeradicals(HO•),non-radicalmolecules(hydrogenperoxide,H2O2,etc.)andsuperoxide(O2•−).Thesemoleculesaretheprincipalbyproductsofvariousmetabolicreactionsoccurringinthemitochondria,peroxisomesandtheendoplasmicreticulum(ER)[31].ROShavebeenwidelyacceptedassecondmessengerswhichareinvolvedinmanydifferentbiologicalevents.LowtomoderatelevelsofROSactassignalingtransductionmoleculesandpromotecellproliferationanddifferentiation,aswellasstresstolerance.However,superfluousROSleadtocelldeaththroughirreversibledamagetoDNA,proteinsorlipids.Therefore,tightlyregulatedROSgenerationanddetoxificationarecrucialforsustainingcellularphysiologicalprocesses.ElevatedROSlevels,duetoimbalanceofROSgenerationorelimination,istermedoxidativestressandisoneofthehallmarksofcancer.Oxidativestresshasbeenproposedtoorchestratetumorigenesisandtumorprogressionthroughdirectorindirectmechanisms.ThefirstlinkbetweenROSandtumorigenesiswasidentifiedin1981,wheninsulinwasfoundtopromotetheaccumulationofH2O2thuspotentiatingtumorcellproliferation[32].TheconventionalthoughtisthatexcessiveROSpromotethemutationofDNAsandleadtoirreversibleoxidationofproteinsandlipids,whichprobablyactivateoncogenicsignalingpathwaysandfacilitatetumorigenesis.However,recentevidencesuggeststhatlowormoderatelevelsofROSinducereversibleoxidativemodificationofproteinswhichaffectstheirfunction,regulatingtumorapoptosis,proliferation,invasion,inflammationanddrugresistance.Mechanistically,proteinspossessredox-sensitivecysteineresiduesthatcanbeoxidizedbyROS.Severaloxidativemodificationpatternshavebeenreported,includingdisulfidebonds,sulfenylation,sulfinylation,sulfonylationandS-glutathionylation.Becauseoftheseredoxmodifications,ROSalterthebiologicalfunctionsofredox-sensitiveproteinsinvolvedinmosthallmarksofcancer(e.g.pyruvatekinaseM2(PKM2)inregulatingmetabolismreprogramming,receptortyrosinekinases(RTK)insustainingproliferativesignaling,p53inevadinggrowthsuppression),therebyregulatingcancercellprogression[33,34,35].TheintrinsiclinksbetweenROSandncRNAswithcancerhallmarksROSandncRNAsinsustainingproliferativesignalingAninitialkeyhallmarksofcancerisconstitutivecellproliferationandavoidanceofgrowtharrest.Innormalcells,thecellcycleprogressandsubsequentproliferationaretightlycontrolledtoavoidaberrantcellgrowthandmalignanttransformation.However,cancercellsmaintainsustainedproliferationviaamplificationormutationofcertaingenes,especiallythoseencodingforkinasesandkinasereceptors,whichhaveattractedalotofattentionaspotentialtherapeutictargets.Cyclin-dependentkinases(CDKs):thedirectregulatorsofcellproliferationregulatedbyROSandncRNAsTheproliferationofcancercellsispreciselycontrolledbyentryofspecificphasesofthecellcyclewhichareregulatedbycyclins,CDKs,andCDKinhibitors(CDKIs).TheCDKs,particularlyCDK1,CDK2,andCDK4/6,areactivatedviabindingtotheirselectedcyclins:cyclinB,cyclinEandcyclinD,respectively,toformfunctionalcomplexeswhichgiveaccesstotheentryofthecellcycle[36].CDKIs,suchasp16,p21,andp27,actasnegativeregulatorsofactivatedCDKsbyspecificallybindingtotheirtargetcyclin-CDKcomplexestoblockthecellcycleprogression[37].Aftertheseregulatorscompletetheirfunctionsincontrollingcellcycle,theyarecommonlyubiquitylatedbyspecificE3ligasesanddegradedviatheubiquitin-proteasomepathway[38].Inadditiontopost-translationalregulation,thesecellcycleregulatorsarealsomodulatedbytranslationalregulationinwhichncRNAsplayafundamentalrole.PreviousstudieshavedemonstratedthatCDK4andCDK6aredirectlyregulatedbyavarietyofncRNAs,someofwhicharecloselyrelatedtocellularROS.Forinstance,itiswell-knownthationizingradiation(IR)inducesROSgenerationincancercellsandmultiplencRNAsmaybedysregulatedunderthisstresscondition[39].ThemiRNAlet-7family,awell-establishedtumorsuppressivencRNA,hasbeenfoundtobedownregulatedunderionizingradiation-inducedoxidativestress,leadingtotheexpressionofCDK6andsubsequentlypromotingcellcycleprogressionofmelanomacells[40].Likewise,5-aminolevulinicacid-mediatedsonodynamictherapy(ALA-SDT)treatedmelanomacellsshowedincreasedintracellularROSlevelsandmiR-34aexpression,whichactedsynergisticallytoinhibittheexpressionofpro-proliferativefactorsCyclinD1andCDK6tosuppresscellcycleprogression[41].Twoothertumorsuppressors,miR-15aandmiR-16weredownregulatedinseveralcancertypes[42,43].OverexpressionofmiR-15aandmiR-16mediatedproductionofmitochondrialROSandinhibitionofcellcycleregulatorsincludingcyclinD1,cyclinE1,cyclinD3andCDK6,therebyinducingcellcyclearrestattheG1phase[44,45].Inaddition,silencingofmiR-21inA549humanlungcancercellsincreasedoxidativedamageandthecellcyclewasblockedattheG0/G1phasebydownregulationofCDK1,thusreversingmultidrugresistanceoflungcancercells[46].Inprostatecancercells,ionizingradiationupregulatedtheexpressionofmiR-17-3p,whichledtocellularROSaccumulationandcellcyclearrestbytargetingmanganesesuperoxidedismutase(MnSOD)andcyclinD1,respectively[47].Incoloncancercells,curcuminoidtreatmentinducedROSproductionwhichdisruptedthemiR-27a/Sp/cyclinB/cdc2axisandinhibitedsubsequentG2-Mtransition,leadingtoenhancedgrowthinhibitionof5-FU[48,49].ExceptformiRNAs,lncRNAsalsoparticipateinregulationofCDKsincancercells.RecentstudyhasfoundthatthelongnoncodingRNA,growtharrest-specifictranscript 5(GAS5)wasdownregulatedinmelanomacells.ThereducedexpressionoflncRNAGAS5contributedtoredoxbalanceandcellcycleprogressionthroughincreasingexpressionofCyclinD1,CDK4,andNOX4,suggestingdownregulatedGAS5andincreasedROSlevelsaspromisingdiagnosisorprognosisbiomarkerformalignantmelanoma[50].InHepatitisCvirus-relatedhepatocellularcarcinoma(HCC),microarrayanalysishasfoundthatlncRNALINC01419andAF070632aremostlyinvolvedwithcellcycleprogressionandoxidation-reduction,althoughtheunderlyingmechanismremainsunclear[51].MALAT1,anevolutionarilyconservedlncRNAthatregulatesmRNAsplicing[52],isupregulatedinseveraltypesofhumancancersandisinvolvedincancercellproliferation.TargetingMALAT1byanovelLNAgapmeRantisenseoligonucleotide(ASO)resultedinincreasedROSlevelsanddecreasedexpressionofB-Myb,whichwasresponsiblefortheexpressionofmitoticproteinssuchascyclinB1,CDK1[53,54].TheseabovefindingsindicatethatcellularROSandncRNAsaretightlyregulatedbyeachotherandbothdirectlymodulateexpressionofCDKseitherpositivelyornegativelyinacontextdependentmanner,thussupportingthecancerhallmark“sustainingproliferation”(Fig. 1). Fig.1InterplaybetweenROSandncRNAsinregulatingcancercellproliferation.Cyclinsandcyclin-dependentkinases(CDKs),especiallyCDK4/6andCyclinB/D1,aredirectlyregulatedbyavarietyofncRNAs,someofwhicharecloselyrelatedtocellularROS.TheimportantrolesofinteractionsbetweenRTKs(includingEGFRandMAPK),ncRNAsandROSincancercellproliferationarepresentedFullsizeimageRTKsaretheupstreamgrowthsensorsregulatedbyROSandncRNAsTheproliferationofcancercells,regulatedbycyclinsandCDKs,alsorequiresstimulationofupstreamsignalsthataresensedbyRTKsaftergrowthfactortreatment[55].DysregulationofRTKs(eithergeneamplificationorsomaticmutations)thatresultsintheirconstitutiveactivationandoncogenicproperties,hasbeenreportedinvarioustumortypes,contributingtotumorgrowth[56].AccumulatingevidencesupportstheimportantroleofinteractionsbetweenRTKs,ncRNAsandROSincancercellproliferation(Fig.1).Theepidermalgrowthfactorreceptor(EGFR)isoneofthemoststudiedRTKs.Itisactivatedbybindingofitsligand,theepidermalgrowthfactor(EGF),resultinginactivationofsignalingpathwayspromotingproliferation[57].StudieshaveshownthatncRNAs,alongwithEGFRandcellularROS,displaycrucialrolesintheprogressionofcancer.Curcuministhemajoractiveingredientinturmericwhichinhibitsgrowthofseveralcancercelllinesbydownregulatingspecificityprotein(Sp)transcriptionfactorSp1anditstargetgenes[58,59].GandhyandcolleaguesfoundthatcurcuminanditssyntheticanalogRL197inducedROSaccumulationincoloncancercells,whichdecreasedexpressionofSp1,Sp3,Sp4andSp-regulatedgenes,includingEGFR[60].Theyfurtherrevealedthatcurcumin−/RL197-inducedsuppressionofSpwasdependentonROSandthesubsequentinductionoftheSprepressorsZBTB10andZBTB4regulatedbydecreasedmiR-27a,miR-20aandmiR-17-5p[60].Likewise,themiR-27a/ZBTB10/Sp/EGFRaxiswasalsoobservedincoloncancercellsaftertreatmentwithethyl2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate(GT-094,anovelnitricoxidechimerathatinducesROSproduction)[61].Inlungcancercells,increasedmiR-551bexpressionreducedtheexpressionofcatalaseandpotentiatedcellularROSlevelsandMUC1expression.UpregulationofMUC1promotedEGFR-mediatedactivationofAkt/c-FLIP/COX-2tosupportcellsurvival,therebyprotectingcancercellsfromdamagecausedbyanticanceragents[62].Inanotherstudy,highROSgenerationinhumanovariancancercellsinhibitedtheexpressionofmiR-199aandmiR-125bbyincreasingpromotermethylationmediatedbyDNAmethyltransferase1.DecreasedexpressionofmiR-199aandmiR-125bthusactivatedERBB2andERBB3topromotetumorprogression[63].Themitogen-activatedproteinkinases(MAPK)/extracellularsignalrelatedkinasesMEK1/2areanotherimportantRTKsinvolvedincellproliferation.Amongthecomplexfamilymembers,RAS/RAF/MAPKisoneofthemajorpathwaysfortargetedcancertherapyandseveralncRNAsareknowntoregulatethissignalingcascade[64].ThethreecanonicalRASfamilygenes(K-RAS,N-RASandH-RAS)arecommonlymutatedandhyperactivatedinseveralcancertypes,amongwhichtheK-RASisoneofthedriversforpancreaticadenocarcinomas[65].AmiRNAarray-basedstudyhasbeenconductedtoidentifydysregulatedmiRNAsunderK-RASactivation.TheauthorsfoundthatmiR-155wasthemostupregulatedmiRNAandcausedinhibitionofFOXO3aanddecreaseofmajorantioxidants(includingSOD2andcatalase),thusenhancingpancreaticcellproliferationinducedbyROSgeneration[66].Inaddition,miR-155alsofunctionsinregulationofglioblastomacellproliferation.KnockdownofmiR-155sensitizesgliomacellstochemotherapywithtemozolomidebyreleasingtheexpressionofMAPK13(alsoknownasp38MAPKδ)andMAPK14(alsoknownasp38MAPKα),twotumorsuppressorgenesthatlowertheaccumulationofROSandinduceapoptosis[67].Inesophagealsquamouscellcarcinoma(ESCC),miR-574-5pwasupregulatedbothinvitroandinvivowhichcorrelatedwithZNF70expression.FurtherstudysuggestedthatupregulationofmiR-574-5ppromotedmitochondrialROSgenerationandMAPKpathways,whichwascloselyrelatedtoZNF70-regulatedcellproliferation[68].AnotherstudyhasshowntheinteractionbetweenoxidativestressandthemiR-200familyinovariancancerprogression.HighexpressionofmiR-141andmiR-200atargetsp38αtomodulatetheoxidativestressresponse,therebypromotingtumorigenesisandchemoresistance.ThiscrucialroleofmiR-200ainstressresponsemayserveasapredictivemarkerforclinicaloutcomeinovariancancer[69].ROSandncRNAsinevadinggrowthsuppressionInadditiontoconstitutivecellproliferation,cancercellsneedtoundergocertaincellulareventstoavoidgrowthsuppressioncausedbytumorsuppressors.Severaltumorsuppressorgenes,includingretinoblastoma(RB)protein,p53andforkheadboxO(FOXO)transcriptionfactors,areinvolvedinsuppressionofcellproliferationoringuidingthecellstoanirreversiblegrowtharresttermedcellularsenescence.ROSincancercellshavebeenreportedtointeractwithncRNAsforpositiveornegativeregulationofthesegrowthsuppressors,therebymodulatingtheevasionofcancercells(Fig. 2). Fig.2InterplaybetweenROSandncRNAsinevadinggrowthsuppression.Tumorsuppressorgenes,includingretinoblastoma(RB)protein,p53andforkheadboxO(FOXO)transcriptionfactorsareinvolvedinsuppressionofcellproliferation,regulatedbytheinterplaybetweenROSandncRNAsFullsizeimageRBprotein-acellcyclegatekeeperregulatedbyROSandncRNAsRB1geneisatumorsuppressorgenewhoseinactivationisresponsibleforoneoftheimportantchildhoodmalignancies,retinoblastoma(Rb).ItexhibitstumorsuppressorfunctionbyrestrictingtheentryfromG1toSphaseofthecellcycle,actingasagatekeeperthatcontrolscellproliferationandquiescence[70].MultipleevidencehasindicatedthatderegulationofvariousncRNAsisinvolvedinRBproteinfunctions.Forexample,knockdownofRBinNSCLCcellsinducedgamma-H2AXfociformation,resultinginROSgenerationandgrowthinhibition,whichwasattenuatedbyoverexpressionofmiR-17-92[71].Inhumantriple-negativebreastcancer(TNBC)cells,theexpressionofhumanlongnoncodingRNALINK-AenhancedK48-polyubiquitination-mediateddegradationoftheantigenpeptide-loadingcomplex(PLC)andintrinsictumorsuppressorsRB[72].InNSCLCH1355andA549cells,treatmentwithchidamide,ahistonedeacetylaseinhibitor(HDACi),inducedROSaccumulationandG1arrestthroughtheregulationofp21andpRBbymiR-129-3p[73].Thetumorsuppressorp16INK4AisanessentialregulatorofRBactivityandplaysessentialrolesinoncogene-inducedsenescence[74].UnderROScondition,p16INK4AgetsactivatedandfunctionsbybindingtoandinhibitingCDK4/CDK6.miR-30,amiRNAfrequentlyoverexpressedinhumancancers,hasbeenfoundtodisruptsenescenceandpromotecancerbysuppressing2targets,CHD7(atranscriptionalcoactivatoressentialforinductionofp16INK4A)andTNRC6A(amiRNAmachinerycomponentrequiredforrepairingoxidativestress-inducedDNAdamage)[75].DownregulationofproteinkinaseCKIIinducescellularsenescenceinhumancoloncancercells.FourmiRNAs(miR-186,miR-216b,miR-337-3p,andmiR-760)werefoundtodegradeCKIIαmRNAbytargetingits3′untranslatedregions(UTRs),therebyincreasingsenescence-associatedβ-galactosidase(SA-β-gal)staining,p21Cip1/WAF1expressionandROSproduction[76].FOXOs:themajormodulatorsofcellfateregulatedbyROSandncRNAsTranscriptionfactorsofFOXOfamiliesaremajorregulatorsofcellgrowthanddeathandcellularredoxhomeostasis[77].FOXOsdisplaytumor-suppressivefunctionsbymediatingthetranscriptionofaplethoraoftargetgenes,includingp16INK4A,p19INK4D,p21CIP1/WAF1,andp27KIP1CKIs,keepingcellsinaquiescentstateintheabsenceofgrowthfactorstimulation[78].ManyncRNAshavebeenidentifiedasregulatorsofFOXOexpression.Forinstance,miR-27aandmiR-96wereidentifiedasregulatorsofFOXO1expressiontogetherwithmiR-182,andwerehighlyexpressedinMCF-7andMDA-MB-231breastcancercells,causingdown-regulationofFOXO1proteinlevelswhichcontributedtomaintenanceofaproliferativestatewhileimpairingapoptoticresponses[79].Ingliomacells,overexpressionofmiR-96,miR-182andmiR-183ledtoadecreasedFOXO1expressionandincreasedcellproliferation,whichwasaccompaniedbylowerROSproductionalthoughFOXOsproteinsareusuallysupposedtobeinvolvedincellularantioxidantresponse[80].Inaddition,oxidativestressinhibitsSTAT5-mediatedmiR-182expression,therebyreleasingFOXO1tosuppressgrowthofhumanSK-N-MCneuroblastomacells[81].Inhumancoloncancercells,inhibitionofaldosereductasesignificantlyincreasedPTENandFOXO3aexpressionviathegrowthfactor-inducedROS/PI3K/AKTaxis,therebydownregulatingmiR-21expressionandinhibitingcoloncancergrowth[82].Inanotherstudy,usingmicroarrays,theauthorsidentifiedmiR-155asthemostupregulatedmiRNAafterbothacuteandprolongedactivationofK-Rasinadoxycyline-induciblesystem.OverexpressionofmiR-155causedinhibitionofFOXO3aandenhancedcellproliferationinducedbyROSgenerationinhumanpancreaticcancercells[66].Additionally,overexpressionofmiR-155inNSCLCcellsincreasedcellproliferationthroughinhibitionofFOXO1andsubsequentproductionofROS[83].p53:apowerfultumorsuppressorregulatedbyROSandncRNAsDuringthepastdecade,mountingevidencehassuggestedthattheinterplaybetweenp53,ncRNA,andROShelpsincontrollingp53-regulatedgenesthataredirectlyorindirectlylinkedtosuppressionofcancercellgrowth.p53,oftencalled“theguardianofthegenome”isthemostwell-knowntumorsuppressortodate[84].Undernormalconditions,p53ismaintainedatalowerlevelduetorapidproteindegradationmediatedbyMDM2[85].However,whencellsencounterstressconditions,p53isstabilizedandactivatedtoprotectcellsfromstress-induceddamageorthecellularapoptoticprocessisinitiatedifthedamageisirreversible,therebypreventingmalignanttransformation[86].miR-16isap53-regulatedmicroRNAandisfrequentlydeletedordownregulatedinHCCcells[87].TreatmentwithsanguinarineinHCCcellsactivatesmiR-16viaincreasedp53occupancyonthemiR-16promoter.UpregulatedmiR-16inhibitedexpressionofitstargetgenes,includingBcl-2andcyclinD1,thusinducingp53-dependentcellcyclearrestandROS-associatedapoptosis[88].Ingastriccancertissuesandcelllines,miR-30isoverexpressed.ThissuppressesmitochondrialdysfunctionandapoptoticeventsbydecreasingROSgenerationandinhibitingp53activation[89].Betulinicacid(BA),apentacyclictriterpene,hasbeenreportedtoshowanti-canceractivityagainstHCC.Mechanisticstudyrevealedthatp53wasresponsiblefortheanti-canceractivityofBAthroughupregulationofmiR-21anddownregulationofSOD2expression,resultinginmitochondrialROSproductionandapoptosis[90].InHCCcells,fourmiRNAs(miR-34a-5p,miR-1915-3p,miR-638,andmiR-150-3p)wereidentifiedastheoxidativestress-responsivemiRNAs,amongwhichmiR-34a-5p,miR-1915-3pareregulatedbyap53-dependentpathway[91].Prolineoxidase(POX)isanovelmitochondrialtumorsuppressorregulatedbyp53whichinhibitsproliferationandinducesROS-dependentapoptosis.IthasbeenreportedthatmiR-23binrenalcancerfunctionsasanoncomiRbydirectbindingtothePOXmRNA3’UTRregion[92].ApartfrommiRNAs,lncRNAsalsoparticipateinregulationofp53function.InNSCLCcells,treatmentwithmarineactinomycetesderived1-hydroxy-1-norresistomycin(HNM)increasedROSgenerationinmitochondriaandupregulatedthep53mediatedtranscriptionalregulationoftwolncRNAs(LEDandLOC285194),leadingtocellcyclearrestandsubsequentapoptosis[93].Ferroptosisisaformofprogramedcelldeathregulatedbyiron-dependentlipidROSaccumulation.ThecytosoliclncRNAP53RRAisatumorsuppressorinlungcancerwhichpromotescell-cyclearrest,apoptosis,andferroptosisviasequestrationofp53inthenucleus[94].Arsenictrioxideshowsmarkedanticanceractivityinthetreatmentofhematologicmalignancies[95].ArecentstudyhasexploredthefunctionsoflncRNAsintheresistancetoarsenictrioxideinlivercancer.TheresultsdemonstratethatarsenictrioxidetreatmentpromotestheexpressionoflncRNARORandtheactivationofp53,bothofwhichareregulatedbyarsenictrioxideinducedoxidativestress[96].LncRNAnuclearenrichedabundanttranscript 1(NEAT1)wasregulatedbyp53inresponsetoDNAdamage[97].EGCG(epigallocatechin-3-gallate),agreenteapolyphenol,wasfoundtoupregulatelncRNANEAT1throughROSgeneration,whichinducedcoppertransporter1(CTR1)expression.EnhancedexpressionofCTR1increasedcisplatinintake,therebypromotingsensitivitytocisplatininNSCLCcells[98].Exceptforp53itself,manypro-andanti-apoptoticfactors(regulatedbyorwhichregulatep53)areknowntointeractwithncRNAsincancer,ofwhichtheB-celllymphoma2(Bcl-2)familyisthemostprominent.ThetumorsuppressormiR-34isatranscriptionaltargetofp53.Capsaicin-inducedoxidativedamageleadstoactivationofp53inNSCLCcells.Upregulatedp53thusenhancesexpressionofmiR-34a,whichinturninhibitsBcl-2expressionandpromotescelldeath[99].TreatmentwithdocetaxelinprostatecancercellsresultedinupregulationofmiR-193a-5p,whichinturnpromotedHO-1inducedexpressionofBcl-2,partlycounteractingapoptosisregulatedbydocetaxel-inducedoxidativestress[100].Inaddition,overexpressionofmiR-33awasobservedinclinicalgliomaspecimensandcelllines,whichnegativelyregulatedtheexpressionofSIRT6viatargetingthe3’UTRmRNA,therebydecreasingROSproductionandincreasingBcl-2expressiontoinhibitapoptosis[101].miR-21wasfrequentlyoverexpressedinseveraltypesofcancer,includinglungcancer,livercancerandbreastcancer[102,103,104,105].InhumanbreastcancerMCF-7cells,miR-21wasdown-regulateduponmetformintreatmentandthisimpededROSproductionandsimultaneouslyinhibitedBcl-2expression,therebyinducingapoptoticcelldeath[103,106].Moreover,ROSpromotegastriccarcinogenesisviaupregulationofmiR-21,whichinturndownregulatedtheexpressionofprogrammedcelldeath4protein(PDCD4),akeyregulatorresponsiblefortranslationofp53mRNAingastriccancercells[107].ROSandncRNAsinresistingcelldeathOncogenictransformationresultsinhigherROSproductionincancercells.WhencancercellsareexposedtohighlevelsofROSthatexceedtheclearancerate,ROSwillbecomedamaging,andthecellularstressresponsemachineryisactivatedwhichmayleadtoapoptosis.Incontrast,cancercellsovercometheinductionofapoptosisbyeitherinactivatingtumorsuppressorgenes,mostnotablyp53asmentionedabove,orelevationoftheapoptoticthresholdbyelevatingexpressionofanti-apoptoticproteinslikeBcl-2familymembers,therebyresistingtransformation-inducedcelldeath.Moreover,cancercellsusuallyundergomutationoramplificationleadingtohyperactivationofantioxidantgenes,mostnotablyNrf2,toevaluatethethresholdofstresstolerance.Nrf2:animportantantioxidantregulatormodulatedbyROSandncRNAsNrf2,amasterregulatorofcellularantioxidantresponse,iscommonlyexpressedinthecytoplasmwhoseactivityisnegativelyregulatedbykelch-likeECH-associatedprotein1(Keap1)[108].Underoxidativestressconditions,cysteineresiduesofKeap1areoxidizedwhichinactivateKeap1function,therebyresultinginstabilizationandsubsequentnucleartranslocationofNrf2[109].Afternucleartranslocation,Nrf2functionsasatranscriptionfactorviabindingtotheantioxidant-response-element(ARE)orelectrophile-responseelement(EpRE),whichfinallytranscribesalmost200genesresponsiblefordetoxification,antioxidation,andmetabolism[110].NcRNAshasbeenfoundtoregulatetheNrf2pathwayforcancermanagement[111].Ithasbeenreportedthatinhumanbreastcancercells,miR-28degradestheNrf2mRNAbybindingtoits3’UTR,whichisindependentofKeap1[112].Similarly,othermiRNAs,includingmiR-507,− 634,and − 129-5p,arealsoknowntonegativelyregulateNrf2-mediatedpathways[113].Cisplatinresistanceisacommonphenomenoninlungcancertherapy.miR-144-3ppreventscisplatinresistanceinlungcancercellsbyinhibitionofNrf2[114].Inaddition,miR-200awasdownregulatedinbreastcancerandre-expressionofmiR-200areleasedNrf2fromKeap1viatriggeringKeap1mRNAdegradation,leadingtonucleartranslocationofNrf2andsubsequenttranscriptionoftargetgenes[115].miR-125bhasbeenfoundtoupregulateperoxiredoxin-like2A(PRXL2A),anantioxidantproteincommonlyupregulatedinoralsquamouscellcarcinoma(OSCC),whichinhibitsthecellularoxidativedamagebypositiveregulationoftheNrf2signalingpathway[116].Treatmentwitharsenite,awell-documentedhumanlungcarcinogen,onhumanbronchialepithelial(16-HBE)cellsresultedinmiR-155-mediatedNrf2inactivation,thusenhancingoxidativedamageandcellmalignanttransformation[117].InMCF-7cells,treatmentwithmetformininducedmiR-34aexpressiontodownregulatetheSirt1/Nrf2pathway,resultinginincreasedsusceptibilityofcancercellstooxidativestressandTRAIL-inducedapoptosis[118].ThemodulatoryeffectoftheNrf2signalingpathwaysonthencRNAshasalsobeenreportedinmanystudies.HDACisarecommonlyusedinthetreatmentofcancer,butdevelopmentofresistanceoftenoccurs[119].InthecaseofHDACistreatment,Nrf2signalingpathwaywasfoundtoactivatemiR-129-3ptotriggerthemTORpathway,therebystimulatingautophagyfordegradationofagedordamagedcomponentsandmacromoleculestosuppresstheoxidativestress,leadingtochemoresistanceofthecancercells[120].IthasbeenshownthattheNrf2signalingpathwayinhibitstheexpressionofmiR-17-5ptodown-regulateFPN1,aniron-exporterprotein,whichresultsintheaggregationofironandROS.DownregulationofFPN1contributestothesurvivalandgrowthofmultiplemyeloma[121].ThesestudiesdemonstratethattheNrf2signalingpathwayandmiRNAsareregulatedbyeachother,andunderstandingtherelationshipbetweenNrf2andmiRNAswillbenefitthedelineationoftheunderlyingmolecularpathwaysandthetreatmentofvariouscancer.InadditiontomiRNAs,lncRNAsarealsoinvolvedinNrf2-regulatedtumorigenesis.LncRNAH19wasfoundtoregulatecisplatinresistancebypromotingNrf2-mediatedgenetranscriptioninhigh-gradeserousovariancancer[122].Inaddition,Nrf2hasbeenshowntoregulatethetranscriptionofsmoke-andcancer-associatedlncRNA-1(SCAL1),whichdecreasesoxidativedamageinlungcancercells[123].InHCCcelllines,itwasfoundthatNRAL,alongnon-codingRNA,contributedtocisplatinresistance.FurtherstudiesrevealedthatNRALfunctionedasaceRNAtonegativelyregulatemiR-340-5pexpressionwhichtriggeredNrf2-dependentantioxidantenzymes,suggestingtheimportantroleoftheNRAL/miR-340-5p/Nrf2axisinthecisplatinresistanceofHCCcells[124,125].AnotherstudyhasfoundthatNrf2inducestheupregulationoflncRNAtaurine-upregulatedgene2(TUG2),whichpromotesprogressionandadriamycinresistanceinurothelialcarcinomaofthebladder[126].Conversely,arecentstudyhassuggestedthatlncRNATUG1bindsdirectlytoNrf2andupregulatesitsproteinexpression,thuscontributingtocisplatinresistanceofESCCcells[127].Moreover,lncRNAKeap1regulation-associatedlncRNA(KRAL)functionedasaceRNAtonegativelyregulatemiR-141whichrestoredKeap1expressionandinhibitedNrf2expression,thusreversing5-FUresistanceinHCCcells[128].InNSCLCcells,miR-335isthedownstreamtargetoflncRNA-XISTandoverexpressedlncRNA-XISTincreasesSOD2(animportanttranscriptionaltargetofNrf2)expressionlevelsbyspongingmiR-335,therebydecreasingROSlevelsandresistingcelldeath[129].TheabovefindingsthereforesuggestthattheinteractionbetweenncRNAs,Nrf2andROSdisplaysacrucialroleforbothpositiveandnegativeregulationoftumorigenesis(Fig. 3). Fig.3InterplaybetweenROSandncRNAsinregulatingNrf-2pathway.TheinteractionbetweenncRNAsandROSdisplaysacrucialroleforbothpositiveornegativeregulationoftheNrf-2pathwaywhichcontributingtothecancerhallmark“resistingcelldeath”FullsizeimageCellstemness:keyfeatureofresistantcancercellswhichregulatedbyROSandncRNAsEmergingevidencehasshownthatasmallpopulationofcellswithstemcell-likeproperties,termedcancerstemcells(CSCs),havethecapacitytoundergoself-renewalwhichcontributestoresistancetoconventionaltherapies[130].IthasbeendemonstratedthatncRNAsregulateCSC-mediatedtherapyresistancebymodulatingtheredoxstateofcancercells[131].Thestem-likecellsinCRCarehighlydependentoncellularGSHtomaintainROSlevels.JuandcolleaguesfoundthatmiR-1297levelswereinverselycorrelatedwiththeexpressionofxCT,acystine/glutamatetransporterrequiredforGSHsynthesis.TheinteractionofxCTwithCD44v,aCSCmarker,effectivelyinducedenrichmentofCRCstem-likecells,whichwasassociatedwithcanceraggressivenessandpoortherapeuticresponses[132].Inanotherstudy,theauthorsfoundthatmiR-153wasdownregulatedanditstargetgeneNrf-2upregulatedingliomastemcells(GSCs)whencomparedtonon-GSCsgliomacells.IncreasedexpressionofNrf2promotedGPX1expressionandsubsequentlyreducedROSproduction,leadingtoradioresistanceofGSCs[133].AfurtherstudyfoundthatoverexpressionofmiR-153inducedROS-mediatedactivationofthep38MAPKpathway,whichsignificantlyreducedstemnessandthusenhancedradiosensitivity[133].Inaddition,miR-128apromotedROSproductionviaspecificinhibitionoftheBmi-1oncogene,whichincreasedtheradiosensitivityofmedulloblastomastemcells[134].Moreover,SunandcolleaguesfoundthatmiR-223expressionwasdownregulatedinTNBCstemcells(TNBCSCs)andoverexpressionofmiR-223resensitizedTNBCSCstoTRAIL-inducedapoptosisthroughthemitochondria/ROSpathway[135].AnotherstudyfoundthattheexpressionofmiR-125awasdecreasedinlaryngealcarcinomatissuesandlaryngealcancerstemcells(Hep-2-CSCs).OverexpressionofmiR-125areversedcisplatinresistanceinHep-2-CSCsbytargetingHematopoieticcell-specificprotein1-associatedproteinX-1(HAX-1,ananti-apoptoticproteinassociatedwithmitochondriaROSproduction)[136].H19,awell-characterizedlncRNAknownforitsroleinembryonicdevelopment,wasshowntobeupregulatedinHCCalongwithERK/MAPKsignaling,whichwasresponsibleforthechemoresistanceofCD133+stemcells.InhibitionofH19downregulatedERKsignalingandpromotedROSproduction,resultinginreversedchemoresistanceofCD133+cells[137].Together,theseresultssuggestthatdysregulationofcellularredoxbalancemayserveasamajorfactorforchemo/radio-resistanceofCSCs.NcRNAs-mediatedredoxstatealterationmayactasanovelstrategytodecreaseCSCspopulation,thusovercomingtherapyresistance.Autophagy:akeypro-survivalprocessregulatedbyROSandncRNAsAutophagy,aconservedintracellularself-digestionprocessresponsiblefortherecyclingofdamagedproteinsororganelles,hasbeenreportedtomediateresistancetochemo/radiotherapy-inducedcelldeath[138].TheinteractionbetweenncRNAsandcellularROSregulatestheautophagyprocessthatdisplaysimportantfunctionsinmodulatingtherapyresistance.Forexample,miR-17-5pisdownregulatedinpaclitaxel-resistantlungcancercells.OverexpressionofmiR-17-5pimprovedsensitivityofthesecellstopaclitaxelviatargetingBeclin1andthesubsequentautophagyprocess,whichwasaccompaniedbyROS-mediatedapoptosis[139].Ingliomacells,inhibitionofmiR-21wasfoundtoenhancetamoxifen-inducedautophagiccelldeathwhichwasaccompaniedbyoxidativestressinductionandJNKactivation,therebyreversingtamoxifenresistanceinhumangliomacells[140].EnvironmentalairborneparticulatematterPM2.5inducedROSproductionthatwasresponsibleforincreasedexpressionoflncRNAloc146880andfurtheractivationofautophagy.Furtherstudyfoundapositivecorrelationbetweenloc146880expressionandLC3Blevelsintumortissuesoflungcancerpatients,indicatinganoncogenicroleofPM2.5-inducedautophagy[141].Inaddition,lncRNASCAMP1activatesZEB1/JUNandautophagytopromotepediatricrenalcellcarcinomaunderoxidativestressviatargetingmiR-429[142].ArecentstudyhasfoundthatmiR-27areversedchemoresistanceofbreastcancercellstodoxorubicinbydisruptingROShomeostasisandimpairmentofautophagy[143].Treatmentofsodiumbutyrate(NaB,aHDACi)inbladdercancercellsinducedAMPK/mTORpathway-mediatedautophagyandROSoverproductionviathemiR-139-5p/Bmi-1axis[144].miR-30ahasalsobeenreportedtoenhancethechemosensitivityofglioblastomacellstotemozolomideviatargetingBeclin-1andautophagy[145].ROSandncRNAsinderegulatingcellularenergeticsMetabolicreprogrammingisoneofthekeyhallmarksofmalignanttumors[146].Unlikenormalcells,cancercellsundergoglycolysistoproducelacticacideveninthepresenceofoxygen.ThiswasfirstdiscoveredbyWarburginthe1920sandtermed“theWarburgeffect”[147].Sincethen,manystudieshavebeenconductedtothoroughlyinvestigatethepossiblerelationshipsbetweenmetabolismandcancerprogression.Metabolismisacentralprocessforcellularredoxhomeostasisandrelatedsignaling,asmitochondriaoxidativephosphorylation(OXPHOS)isoneofthemajorsourcesofROS[148].Moreover,cellularreductants(suchasNADPHandGSH)aresynthesizedbymetabolicintermediatesgeneratedinmultiplemetabolicprocesses[149].BesidesROS,ncRNAsarealsoinvolvedinregulationofmetabolicreprogramming,suggestingapossiblerolefortheinterplaybetweenncRNAsandROSinmodulationofmultiplemetabolicprocess(Fig. 4). Fig.4InterplaybetweenROSandncRNAsinregulatingcellmetabolism.Cancercellmetabolism(includingglucose,aminoacidandlipidmetabolism)aretightlyregulatedbytheinteractionbetweenROSandncRNAs,whichgenerateenergyormetabolicintermediatestosupportcancercellgrowthFullsizeimageRegulationofglucosemetabolismbyROSandncRNAsNcRNAselaboratelyregulatecancer-associatedglycolyticpathwaysbymodulatingexpressionofspecificmetabolicenzymesortranscriptionfactorsresponsibleformasterregulationofcellmetabolism.Inpancreaticductaladenocarcinoma(PDAC)cells,itwasobservedthatglutaminedeprivationresultedinaccumulationofROSinMIA-PaCa-2cells,whichpromotedmiR-135expression.ROS-mediatedupregulationofmiR-135targetedphosphofructokinase1(PFK1)andsuppressedaerobicglycolysis,therebypromotingtheutilizationofglucosetosupportthetricarboxylicacid(TCA)cycle[150].AnotherstudyfoundthatoverexpressionofmiR-422aingastriccancercellsrepresseditstargetpyruvatedehydrogenasekinase2(PDK2)torestoreactivityofthepyruvatedehydrogenase(PDH),whichshiftedtheenergymetabolismfromaerobicglycolysistooxidativephosphorylation[151].ThemiR-422a/PDK2axisalsoinfluenceddenovolipogenesisincancercells,whichsubsequentlyaffectedROSgenerationandRBphosphorylation,resultingincellcyclearrestattheG1phase[151].AccumulationofROSduetoglucosedeprivationleadstodecreasedHDACsactivity,andparticularlyreducedlevelsofHDAC2,whichresultsintheincreasedacetylationofmiR-466 h-5ppromoterregionandupregulationofthismiRNA[152].Inhypoxicbreastcancercells,oxidativestress-inducedoverexpressionofmiR-181cblockedHIF-1αaccumulationanddiminishedhypoxia-induciblelevelsofglycolysisenzymes,includingglycolysis-associatedglucosetransporter-1(GLUT1),hexokinase2(HK2),PDK1,andlactatedehydrogenaseA(LDHA)[153].ColorectalcancercellsshowreducedexpressionofmiR-1andmiR-133b.EctopicexpressionofthesemiRNAsresultsinROSgenerationtosilencepolypyrimidinetract-bindingprotein1(PTBP1),whichconvertsactivePKM2toinactivePKM1,thusinducinggrowthsuppressionandautophagiccelldeath[154].Likewise,miR-1andmiR-206aretranscriptionaltargetsofNrf2inlungcancercells.SustainedactivationofNrf2signalingattenuatedmiR-1andmiR-206expressionwhichdirectedcarbonfluxtowardthepentosephosphatepathway(PPP)andtheTCAcycle,contributingtocellularredoxhomeostasisbyenhancingNADPHproduction[155].ThisfindingrepresentsanovellinkbetweenmiRNA,ROSandglucosemetabolismincancercells.miR-199a-3pexhibitedinhibitoryeffectsonlacticacidproduction,glucoseintakeandROSlevelsintesticularcancerNtera-2cells.FurtherstudyfoundthattranscriptionfactorSp1wasthedirecttargetofmiR-199a-3p,whichdecreasedLDHAproteinexpression[156].EctopicexpressionofmiR-143inrenalcellcarcinomaresultedintheperturbationofglucosemetabolismbynegativelymodulatingtheexpressionofGLUT1andthePTBP1/PKMsaxis,whichshiftedglycolysistooxidativephosphorylationandinducedautophagythroughincreasingROSlevels[157].UsingmicroRNAprofiling,TangandcoworkersfoundthatmiR-320ainhibitedoxidativestress-inducedPFK(arate-limitingglycolyticenzyme)expressioninlungcancercells[158].Treatmentwithastragalin,abioactivecomponentofmedicinalplantssuchasRosaagrestis,resultedinincreasedmiR-125bwhichrepressedHK2expressionanddirectedglycolysistooxidativephosphorylation,leadingtoROSaccumulationandgrowthsuppressionofHCCcells[159].Inhumanlungadenocarcinomas,miR-182negativelyregulatesPDK4andpromotesdenovolipogenesisofcancercells,whichisaccompaniedbyincreasedROSlevelandJNKactivation[160].TNBCandmetastaticmelanomacelllinesshowoverexpressionoflet-7awhichrepressescellproliferation,increasesROS,anddownregulatesproteinsinvolvedinglucosemetabolismincludingglucose6-phosphatedehydrogenase(G6PD)[161].LncRNAIDH1-AS1,atranscriptionaltargetofc-Myc,promotedhomodimerizationofIDH1andenhanceditsenzymaticactivity,whichresultedinincreasedα-KGanddecreasedROSproduction,leadingtoattenuationofglycolysis[162].Inaddition,prostatecancergeneexpressionmarker1(PCGEM1),anandrogen-inducedprostate-specificlncRNA,hasbeenshowntopromoteglucoseuptakeforaerobicglycolysis,whichisaccompaniedbytheshuntofpentosephosphatetofacilitatebiosynthesisofnucleotidesandlipids,andgenerateNADPHforredoxhomeostasis[163].RegulationofaminoacidmetabolismbyROSandncRNAsAsanotherimportantcellularenergysource,aminoacidsalsoplayacrucialroleforthesurvivalandproliferationofcancercells.Onecrucialaminoacidisglutaminewhichisconvertedintoglutamatebytheratelimitingenzymeglutaminase(GLS1/GLS2).IthasbeenreportedthatoverexpressionoflncRNAurothelialcarcinoma-associated1(UCA1)promotedtheexpressionofGLS2inhumanbladdercancercells.FurtherstudyrevealedthatUCA1functionedasamiR-16spongetoreduceROSproductionandinduceGLS2expression,leadingtoincreasedglutaminolysisinbladdercancercells[164].Inarecentstudy,theauthorsfoundthatmiR-9-5pwassignificantlydownregulatedinpancreaticcancertissuesandcelllines.OverexpressionofmiR-9-5pinhibitstheexpressionlevelofGOT1mRNAbydirectbindingtoits3’UTR,thusaffectingtheglutaminemetabolismandredoxhomeostasisinpancreaticcancercells,suggestingthatmiR-9-5pmayserveasaprognosticortherapeutictargetforpancreaticcancer[165].InMYC-drivenlivertumors,theexpressionofGCLC,arate-limitingenzymeofGSHsynthesis,isattenuatedbyMYC-inducedmiR-18aexpression,whichcontributestoGSHdepletionandcorrespondswithincreasedsensitivitytooxidativestressintumors[166].Ferroptosisisaregulatedformofcelldeathdependentonlipid-basedROSaccumulation.IthasbeenreportedthatmiR-137negativelyregulatesferroptosisbydirectlytargetingglutaminetransporterSLC1A5inmelanomacells,andknockdownofmiR-137increasestheantitumoractivityoferastinbyenhancinglipidROS-inducedferroptosisbothinvitroandinvivo[167].Ingastriccancercells,treatmentofphyscion8-O-β-glucopyranoside,acommonanthraquinonefoundinvariousplants,decreasedexpressionofmiR-103a-3pwhichreleasedtheexpressionofGLS2andpromotedROSlevelandsubsequentferroptosis[168].ROSandncRNAsininducingangiogenesisWhenatumorgrowstoacertainsize,theprimaryproximalbloodvesselsareinsufficienttosupportenoughnutrientsandoxygen[169].Tumorcellsthensecretpro-angiogenicfactorstostimulatenewbloodvesselformation,whichistermedangiogenesis,animportanthallmarkofcancer[170].Thenewlyformedbloodvesselsprovidesoxygenandnutritionfortumorgrowthandremovemetabolicwastefromthetumormicroenvironment[171].Fibroblastgrowthfactor2(FGF2),vascularendothelialgrowthfactor(VEGF)andEGFarethethreemostpotentpro-angiogenicfactorsinthevascularizationoftumors[172].Inaddition,thehypoxiainduciblefactor(HIF)complexisamajorregulatorofpro-angiogenicgenesunderlowoxygenconditions[172].GrowingevidencehasdemonstratedthecrucialroleoftheinteractionbetweenROSandncRNAsininducingtumorangiogenesis(Fig. 5). Fig.5InterplaybetweenROSandncRNAsinregulatinginflammationandangiogenesis.ROSandncRNAsregulatecancerinflammationandangiogenesismainlybytargetingNF-κB,HIF-1αandVEGFRsignalingFullsizeimageVEGF:apivotalgrowthfactorinvolvedinangiogenesisregulatedbyROSandncRNAsVEGFactsasaneffectortostimulatecellproliferationandangiogenesisbybindingtoitstransmembranereceptor,VEGFR.InNSCLCcells,ROS-inducedoverexpressionofhemeoxygenase-1(HMOX1)contributedtop53-mediatedinhibitionofmiR-378expression,whichreducedVEGFexpressionanddiminishedangiogenicpotential[173].AshortageofnutritionandoxygeninglioblastomacellmayleadtoROSaccumulation.Underthisstresscondition,cancercellsdisplayedincreasedlevelsofmiR-17whichtargetedPTENtoupregulateVEGFtosupportcancerprogression[174].Inaddition,treatmentoftubeimoside-1,atraditionalChineseherb,inducedROSaccumulationandincreasedexpressionofmiR-126-5p,whichactedsynergisticallytotargetanddownregulateVEGF-AandVEGF-R2,leadingtogrowthinhibitionofNSCLCcells[175].Similarly,treatmentwithcurcuminoidsincoloncancercellsinhibitedcancerprogressionbydisruptingtheROS/miR-27a/SpaxiswhichmediatedtheinhibitionofVEGFsignaling[48].ERstress-inducedsuperoxidesareconvertedintoperoxidesbyTNF-α-mediatedSODactivation.miR-21hasbeenreportedtoinhibitTNF-α,whichpreventstheconversionofsuperoxidetoperoxide,leadingtoreducedbindingofVEGF/FGF2totheirreceptors[176].Inaddition,thereareseveralanti-angiogenicmiRNAs,includingmiR-497,miR-503,andmiR-126,whichinhibittheROS-mediatedfeedbackloopofVEGFA/FGF2[177,178,179].Anotherreportindicatedthatgenotoxicstress-inducedmiR-494expressionsuppressedDNArepairandangiogenesisthroughregulationoftheMRE11a/RAD50/NBN(MRN)complexwhichpositivelycorrelatedwithVEGFsignaling[180].LncRNAH19inhibitsoxidativestressincancercells.GliomacellsshowupregulationofH19,whichactasaceRNAforinhibitionofmiR-138,leadingtoactivationofVEGFsignalingandsubsequentgliomaangiogenesis[181].InhibitionoflncRNAMALAT1hasbeenreportedtoincreasecellularROSlevels.HCCcellsupregulatedMALAT1topromoteVEGF-AexpressionandangiogenesisviaspongingmiR-140[182].RegulationofHIF1-αbyROSandncRNAsHypoxiaisakeyfactorrequiredforangiogenesis.ItinducestranscriptionfactorHIF1toactivatetheexpressionofpro-angiogenicfactors,especiallytheVEGFfamily,therebyregulatingtumorangiogenesis[183].TheHIF-1complexisaheterodimericproteinconsistingoftwosubunits,HIF-1αandHIF-1β.Undernormoxiaconditions,thestabilityofHIF-1αisaccuratelycontrolledbyprolylhydroxylaseenzymes(PHDs)-mediatedhydroxylationandsubsequentproteasomedegradation[171].IthasbeenreportedthatHIF-1αisstabilizedbyROS,asCys326ofPHD2isoxidizedbyROSleadingtoinactivateddimerizationwhichresultsinHIF-1αaccumulationandsubsequentnucleartranslocation[184].Inaddition,growingdatahavesuggestedthatHIFsignalingisabletoregulatecellularROSlevels,whichmayinfluencethetranscriptionofseveralncRNAs.Forexample,treatmentwithEGCGinlungcancercellsinducesROSaccumulationwhichstabilizesHIF-1α.StabilizedHIF-1αthusbindstohypoxiaresponseelement(HRE)inproximitytomiR-210promoter,leadingtooverexpressionofmiR-210andreducedcellproliferation[185].Similarly,miR-224wasupregulatedbyhypoxiaandHIF-1αingastriccancer.IncreasedexpressionofmiR-224targetedRasassociationdomainfamilymember8(RASSF8)topromotegastriccancercellgrowth,migrationandinvasion,suggestingmiR-224asapotentialtherapeutictargetforhypoxicgastriccancerpatients[186].HIF-1αwasalsofoundtorepressmiR-34aexpressioninp53-defectiveCRCcells,whichactivatedSTAT3pathwayandpromotedEMTandmetastasis[187].Inaddition,thetranscriptionoflncRNAHOTAIRisalsoregulatedbyHIF1αwhichbindstotheHREpresentintheHOTAIRpromoterunderhypoxia[188].SimilarfindingsarealsoreportedinpancreaticcancerinwhichthetranscriptionoflncRNABX111isinducedbyHIF-1αinresponsetohypoxia[189].Incontrast,ncRNAsarealsofoundtobeinvolvedintheregulationofHIF-1αandrelatedsignaling[190].ThioredoxinisknowntoreduceROSlevelsincancercells,therebycontrollingredoxhomeostasis.miR-373hasbeenfoundtobindtothe3’UTRofthioredoxininteractingprotein(TXNIP)anddownregulateitsexpression,whichactivatesHIF-1αtopromotecancerprogression[191].miR-497regulatescisplatinchemosensitivityincancercellsinaROS-dependentmanner.WuandcolleaguesfoundthatectopicexpressionofmiR-497inbreastcancercellsreducedHIF-1αandVEGFproteinlevels,therebysuppressingangiogenesis[192,193].TheinteractionbetweenmiR-21andROShasbeenreportedinseveralcancertypes.StudieshavefoundthatoverexpressionofmiR-21inDu145humanprostatecancercellsincreasedtheexpressionofHIF-1αandVEGF,andinducedtumorangiogenesis[194].Ingastriccancercells,lncRNAzincfingerE-box-bindinghomeobox 2antisenseRNA1(ZEB2-AS1)wasoverexpressedandinhibitedmiR-143-5pexpressionbyactingasamiRNAsponge,whichincreasedROSlevelsandHIF-1αexpressiontopromotecancerprogression[195].Thehypoxia-induciblefactor-2αpromoterupstreamtranscript(HIF2PUT)isanovellncRNAwhichfunctionsinangiogenesisbyregulatingthetranscriptionalactivityofitshostgeneHIF-2α[131,196].OverexpressionofHIF2PUTpromotesHIF-2αexpressiontoactivatetranscriptionofmanypro-angiogenicfactorsunderhypoxiaconditions[197].LncHIFCAR(longnoncodingHIF-1αco-activatingRNA)wasalsofoundtoactasaHIF-1αco-activatorwhichpromotedHIF-1αactivationandoralcancerprogression[198].ROSandncRNAsintumor-promotinginflammationPersistentchronicinflammation,eitherintumorcellsorthetumormicroenvironment,hasbeenrecognizedasakeyregulatorfortumorigenesisandbeensummarizedasoneofthecancerhallmarks[1].Underchronicinflammationcondition,ROS(orRNS)aregeneratednotonlyfrominflammatorycellsbutalsoepithelialcells,whichmaycausebiomacromoleculedamageandepigeneticalterations,therebyinducingcelltransformationandmalignancy[199].Theinflammatoryprocessesregulatecancerprogressionbasedonthelevelofinflammation-relatedfactors,cytokines,andchemokinesproducedfromtumorcellsorcellsinthetumormicroenvironment[9].Inaddition,severaltranscriptionalfactors,includingNF-κB,activatorprotein-1(AP-1)andmembersoftheSTATfamilies,areinvolvedinregulatinginflammatoryresponsebycontrollingtheexpressionofinflammation-relatedfactors[200].DysregulatedexpressionofncRNAsandtheirinterplaywithROShavebeenlinkedtoinflammationandtumorigenesis(Fig.5).NF-κB:themasterregulatorofinflammationwhichregulatedbyROSandncRNAsThetranscriptionfactorNF-κBisprobablythemostwell-knownsignalingfactorinresponsetoinflammationandisconservedinallmulticellularanimals[201].NF-κB-regulatedinflammationresponsemayplayadouble-edgedroleincancerprogression.Ontheonehand,activationofNF-κBtargetsandeliminatestransformedcellsbyinducingcytotoxicimmunecellsunderacuteinflammatoryprocesses[202].Ontheotherhand,constitutiveactivationofNF-κBiscommonlyobservedinmanytypesofcancerwhichexertsavarietyofpro-tumorigenicfunctions[201].AccumulatingevidencesuggeststhattheinterplaybetweenROS,ncRNA,andNF-κBcontributestotumorigenesis.SeveralmiRNAshavebeenshowntobetranscriptionaltargetsofNF-κB.Forinstance,ithasbeenshownthatsaturatedpalmiticacidtriggersgenerationofROSandactivationofNF-κBinpancreaticcancercells.Furthermore,activationofNF-κBdownregulatesmiR-29c,anegativeregulatorofextracellularmatrixproteinsMMP-9,therebypromotingpancreaticcancerprogression[203].Similarly,K-RassignalinginpancreaticcanceractivatesNF-κB,whichresultsinenhancedmiR-155expression,repressedFOXO3expressionandincreasedROSaccumulation[66].Inaddition,increasedexpressionofmiR-21isadownstreameventofROS-mediatedNF-κBactivationandexhibitsacrucialroleinarsenic-inducedneoplastictransformationinhumanlungembryofibroblastcells[204].Similarly,treatmentofhumanmultiplemyelomacelllineU266withberberineresultedinSet9-mediatedlysinemethylationoftheRelAsubunit,whichinhibitedNF-κBnucleartranslocationandmiR-21transcription,therebyinducingROSgenerationandgrowthsuppression[205].Furthermore,NF-κBalsopromotestheexpressionofproteinsthatregulatemiRNAs.ThemostimportantexampleistheNF-κB-dependentinductionoflin28,whoseexpressioninhibitsthematurationoflet-7miRNAs.AsIL-6isoneofthetargetsoflet-7miRNAs,thereducedexpressionoflet-7leadstohigherlevelsofIL-6andfurtheractivationofNF-κB,thereforegeneratingapositivefeedbackloop[206].InadditiontoregulatingmiRNAsdirectlyorindirectly,NF-κBactivityitselfisregulatedbyseveralmiRNAs.Forexample,p53-mediatedmiR-506overexpressioninducesROSaccumulationvianegativeregulationofNF-κB(p65),therebyexhibitingatumorsuppressiveroleinlungcancercells[207].UpregulationofmiR-223promotedmitochondriaROSproductionandsuppressedthephosphorylationofRelA,whichinhibitedNF-κB-regulatedtranscriptionofpro-inflammatorygenes,includingIL-1β,IL-6,TNF-α,andIL-12p40[135,208].miR-9overexpressionpromotesROSproductioninmultiplemyeloma,whichtargetsTRIM56andactivatestheNF-κBpathwaytopromotethedevelopmentandprogressionofmultiplemyeloma[209].Inaddition,ROS-mediatedupregulationofmiR-124-3pspeciallybindstothe3’UTRregionofneuropilin-1andsuppressitsexpression,whichnegativelyregulatesPI3K/Akt/NF-κBpathways,leadingtogrowthsuppressioninGBMcells[210,211].miR-17-92hasbeenfoundtodecreaseROSlevelsincancercells.OverexpressionofthemiR-17-92targetstumornecrosisfactorreceptorassociatedfactor3(TRAF3)andreleaseitsinhibitionontheNF-κBsignalingpathway,thuspromotinggastriccancerprogression[71,212].RegulationofAP-1/STAT:essentialtranscriptionfactorsforinflammatoryresponseTheactivationofthetranscriptionfactorAP-1andmembersoftheSTATfamiliesareessentialformaintainingcellularhomeostasisunderinflammatoryconditions[213].DysregulationofJAK/STATsignalinghasbeenimplicatedintheregulationofinflammatoryresponseinmalignantcellsandncRNAshavebeendemonstratedtotargetimportantplayersinthispathway.Forexample,overexpressionofmiR-124wasfoundtoinhibittheexpressionofSIRT1andthuspromotedthegenerationofROS,whichinducedmiR-124bindingtothe3’UTRregionofSTAT3andinhibitedtheexpressionofSTAT3proteins,resultinginreducedcellproliferationinHCCcells[214,215].Inaddition,overexpressionofmiR-33awasobservedinclinicalgliomaspecimensandcelllines,whichnegativelyregulatedtheexpressionofSIRT6bytargetingitsmRNA3’UTR.FurtherstudyfoundthatoverexpressionofSIRT6reducedcellsurvivalandinitiatedapoptosisbyenhancingROSlevelandinhibitingtheJAK3/STAT3pathway[101].ThelncRNAUCA1reducedROSproductionincancercells.IthasbeenreportedthatUCA1actsasmiRNAspongetoinhibitmiR-126expression,thusactivatingJAK/STATsignalingpathwaysandpromotingcellproliferationinhumanleukemiacells[216].Moreover,treatmentwithaspirinpromotesROSproductionandactivateslncRNAOLA1P2expression.OLA1P2upregulationmarkedlyinhibitsthenucleartransportofphosphorylatedSTAT3bybindingtoandpreventinghomodimerizationofphosphorylatedSTAT3,thusinhibitingSTAT3signalingandsuppressingcancerprogression[217].ROSandncRNAsininvasionandmetastasisMetastasisisacomplexandmultifacetedeventwhichinvolvestheprocessofinvasion,intravasationintoblood,extravasationtodistantorgansandgrowth[218].Aprerequisitechangebeforemetastasisistheactivationofepithelial-mesenchymaltransition(EMT)incancercells,aphenotypictransitionofepithelialcellstoacquiremoreaggressivemesenchymalcharacteristics[218].Inaddition,colonizationofmetastaticcellsisanotherimportantprocess,whichallowstheformationofmetastaticnichesindistantorgans[219].ThemultistepprocessofmetastasisisregulatedbyseveraltranscriptionalfactorssuchasSnail,Slug,ETS-1,Twist,ZEB1andZEB2[220,221,222,223].Moreover,severaltargetsofthesetranscriptionalfactorsarecloselyrelatedtothemetastaticprocess,suchasmetalloproteases(MMP-2/9)andchemokinesorcytokinesliketransforminggrowthfactorbeta(TGF-β)[224,225].Alongwithprotein-codinggenes,somencRNAsmayparticipateincancermetastasisandtheinterplaybetweenROSandncRNAsincancermetastasishasbeendocumented(Fig. 6). Fig.6InterplaybetweenROSandncRNAsinregulatinginvasionandmetastasis.TheinteractionbetweenncRNAsandROSindicatesacrucialroleforbothpositiveornegativeregulationofWntandTGF-βpathwaystomodulateinvasionandmetastasisofcancercellsFullsizeimageRegulationofTGF-βsignalingbyROSandncRNAsTGF-β,animportantpleiotropiccytokine,regulatescellproliferation,celladhesion,cellmigration,andthedifferentiationofaplethoraofdifferentcelltypes[226].Generally,canonicalTGF-βsignalingpromotestheexpressionofmesenchymalmarkers(suchasN-cadherinandvimentin)andreducestheepithelialmarkers(likeE-cadherin)viatranscriptionfactorSMADfamilyproteins[227].TGF-βsignalingdisplaysadouble-edgedroleinregulationtumorigenesis.Itactsasatumorsuppressoratearlystagesofcancerbyinducingcytostasisandapoptosis.However,atlaterstages,itfunctionsasanoncoproteinbysupportingcancergrowthandinducingmetastasis,therebypromotingthedevelopmentandprogressionofcancer[226].TGFsignalinghasbeenreportedtocloselyinteractwithROSandncRNAinregulatingcancermetastasis.Forexample,upregulationofmiR-200familyispositivelycorrelatedwithincreasedROSlevelsuponchemotherapyorradiotherpyincancercells[228].TGF-βhasbeenfoundtodownregulatemiR-200familymembers,includingmiR-200a/−200b/−200c/− 141/− 429,whichpromoteZEB1andZEB2expressionandsubsequentcancerprogression[229].TGFsignalingandROSupregulatemiR-182expression,whichsustainsNF-κBactivationbydirectlysuppressingcylindromatosis(CYLD,anNF-κBnegativeregulator)[230].OverexpressionofmiR-182alsoreduceSMAD7expressionandpromotebreastcancerinvasionandTGF-β-inducedbonemetastasis[231].TGFsignalingandROSalsoinducetheexpressionandpromoteractivityofmiR-155,whichreducesRHOAexpressionanddisruptstightjunctions,leadingtoinvasionandmetastasisofbreastcancer[232].TheexpressionofmiR-206isregulatedbyNrf2underoxidativestressconditions[155].miR-206hasbeenfoundtoinhibitautocrineproductionofTGF-βanddownstreamneuropilin-1(NRP1)andSMAD2expression,leadingtodecreasedmigration,invasion,andEMTinbreastcancercells[233].InprimarymyelofibrosisCD34+cells,TGF-βsignalingenhancesmiR-382-5pexpressionandreducesitstargetgeneSOD2activity,leadingtoROSoverproduction[234].Guoetal.demonstratedthatthekallistatinprotein(aplasmaprotein)inhibitedTGF-βsignalingandROSproductionviaitsheparin-bindingsite,whichfurtherblockedmiR-21andAKTsignaling,thussuppressingEMT[235].Inanotherstudy,metformin-inducedSODoverexpressionquenchedROSlevelsandblockedtheTGFpathway,whichinhibitedmiR-21andMMP-2/9expression,leadingtosuppressionofcellproliferationand/ormigration[106].InirradiatedNSCLCcells,accumulationofROSresultsintheactivationofTGFsignalingandsubsequentoverexpressionofmiR-21,whichleadstoDNAdamage[236].ROS-induceddecreaseinc-MycexpressiondownregulatesmiR-20a[237].TGF-βandoneofitsreceptors(TGFBR2)werefoundtobedownregulatedbymiR-20aviadirectbindingofmiR-20atoits3’UTR,thusabrogatingtheTGF-βsignalinginbreastcancercells[238].OverexpressionofmiR-210resultsinanincreaseofROSgenerationincancercells[239].UpregulatedmiR-210targetsproteininteractionwithPRKCA1(PICK1),acriticalnegativeregulatoroftheTGF-βpathway,andinhibitsitsexpression.ThisactivatesTGF-βsignalingandpromotesbonemetastasisofprostatecancer[240].miR-17-5phasbeenfoundtoincreaseROSlevelsbyinhibitingthreemajorantioxidantenzymes,MnSOD,GPX2,andTrxR2[47].AluciferasereporterassayidentifiedTGFBR2asitstargetandoverexpressionofmiR-17-5psignificantlyenhancedcervicalcancercellproliferationandmetastasis[241].Moreover,miR15a/16hasbeenfoundtoinducemitochondrialROSproductionandreducetheexpressionofendogenousSmad3,therebyinhibitinginvasionofprostatecancercellsbysuppressingtheTGF-βsignalingpathway[44,242].InadditiontomiRNAs,ROSandlncRNAsarealsoinvolvedinregulationofTGF-βsignalingduringcancerprogression.OverexpressionofmiR-139-5psignificantlyincreasedoxidativestressviatargetingROSdefensepathways[243].LncRNANEAT1functionsasaceRNAbyspongingmiR-139-5p,whichupregulatesTGF-β1topromoteHCCprogression[244].InhibitionoflncRNAMALAT1hasbeenreportedtoincreasecellularROSlevels.UpregulatedTGF-βinheadandnecksquamouscellcarcinoma(HNSCC)maypromoteSTAT3activation,whichbindstotheMALAT1promoterandactivatesitsexpression,therebyinducingEMTandacceleratingHNSCCmetastasis[245].TheexpressionofmiR-1isregulatedbyNrf2[155].LncRNAUCA1functionsasaceRNAfortitratingmiR-1andmiR-203atoincreaseSlugexpression,whichpromotesTGF-β-inducedEMTandinvasioninmetastaticbreastcancer[246].miR-421decreasesROSlevelsbytargetingKEAP1expression[247].IthasbeenfoundthatlncRNAMEG3functionsasaspongeofmiR-421toregulateE-cadherinexpression,therebypromotingTGF-β-inducedEMTinbreastcancer[248].miR-372hasbeenfoundtodecreaseROSlevelsbytargetingp62incancercells[249].LncRNAlnc-SNHG1significantlypromotestheexpressionofTGFBR2andRAB11AviaspongingmiR-302/372/373/520,thusactivatingEMTininvasivepituitarycancer[250].AnotherstudyfoundthatlncRNAXISTfunctionsasanceRNAtoinhibitmiR-137expressionanddecreaseROSlevelssimultaneously,whichpromoteZEB2expressionandsubsequentTGF-β-inducedEMTinNSCLCcells[251,252].RegulationofWnt/β-cateninsignaling:awell-knownregulatorfortumormetastasisWnt/β-cateninsignaling,anevolutionarilyhighlyconservedpathway,controlsamultitudeofdevelopmentalprocesses,includingembryonicdevelopmentandmaintenanceofadulttissuehomeostasis[253].Wntsignalingisstage-specificorcancertype-specificandfunctionsbyregulatingtheexpressionofspecifictargetgenes,suchasc-myc,E-cadherin,andcyclinD1[254,255].NcRNAshavebeenfoundtocontributetoboththeactivationandinactivationofWntsignalingforregulatingtumorigenesis.IthasbeenshownthatERstresscanupregulatemiR-346expression,whichreducesROSlevelsthroughmitophagy[256].ERstressalsoenhancesglycogensynthasekinase-3beta(GSK3β)expression,andGSK3βinhibitionreversestheeffectsofmiR-346onROSproduction,suggestingtheroleofWntsignalinginregulatingcancerprogressionthroughthemiR-346/ROS/GSK3βaxis[256].miR-146adownregulatestheexpressionofSOD2andenhancesROSgenerationincancercells[257].IthasbeenreportedthatSnailcaninducetheexpressionofmiR-146athroughβ-catenin/TCF4,whichinturnstabilizesβ-cateninandformsapositivefeedbackcircuit,leadingtosustainedactivationofWntsignalinginCRCstemcells[258].GenerationofROSactivatesmiR-199/214transcription.ThelncRNADANCRbindstothe3′TURofCTNNB1mRNAandblockstheinhibitoryeffectofmiR-214andmiR-199,whichinturnincreasesCTNNB1proteinlevelsandpromotessubsequentactivationofWntsignalinginHCCcells[259].Inaddition,miR-34atargetsNOX2toenhanceROSproduction[260].ThelncRNA-MUF(mesenchymalstemcell-upregulatedfactor)canactasaceRNAformiR-34aandpromoteEMTbyupregulatingSnail1expressionandactivatingWnt/β-cateninsignaling[261].Inadditiontotheabovesignalingevents,thereexistseveralothermetastasis-associatedfactorsthatinteractwithncRNAsincontrollingcancerprogression.miR-21,awell-knownoncogenicmicroRNAcontributingtocarcinogenesisinprostateandothercancers,wasupregulatedbyROS-mediatedAktactivation,whichcontributedtothehighlyinvasiveandmetastaticphenotypeofprostatecancercellsbydownregulationofmaspinandPDCD4[262].Secretedproteinacidicandrichincysteine(SPARC)isamatrixproteinwhichmediatesdiversecellularfunctionsandhasanimportantroleinregulationofcell-matrixinteractionsandmigration.AnoncogenicmicroRNAmiR-155hasbeenreportedtodecreasetheexpressionoftumorprotein53inducednuclearprotein1(TP53INP1),ap53targetgeneresponsibleforthep53-drivenoxidativestressresponse,therebyupregulatingSPARCexpressionandpromotingsubsequentcellmigrationinpancreaticadenocarcinoma[263].lncRNAH19andHULCwereupregulatedbyoxidativestressandregulatedcholangiocarcinomacellmigrationandinvasionbytargetingIL-6andCXCR4viaceRNApatterns,whichspongelet-7a/let-7bandmiR-372/miR-373,respectively[264].ROSandothertypesofncRNAsinregulatingcancerhallmarksAlthoughmiRNAsandlncRNAsarethemaintypesofncRNAsinteractingwithoxidativestresstoregulatecancerhallmarks,otherncRNAsarealsofoundtointeractwithoxidativestressforregulationofcancerprogression,suchascircRNAs.AstheuniquestructureofcircRNAsthatcontaincovalentlyjoined3′and5′ends,itisrationaltohypothesizethatcircRNAsregulatecancerprogressionbyactingasmiRNAsponges[265].Indeed,circRNAsareimplicatedinavarietyofcancers(includinggastriccancer,hepatocellularcancer,bladdercancer,andesophagealcancer,andothers)[266,267].Forexample,knockdownofcircularATPbindingcassettesubfamilyBmember10(circABCB10)promotedlipidROSproductionandsubsequentferroptosisbyregulatingthemiR-326/CCL5axisinrectalcancer,indicatingcircABCB10asapromisingtherapeutictargetforrectalcancer[268].Similarly,circ-TTBK2wasupregulatedingliomatissuesandcells.Furtherstudyfoundthatcirc-TTBK2wasaspongeofmiR-761tomodulateITGB8,andknockdownofcirc-TTBK2inducedlipidROSproduction,whichpromotedferroptosisandretardedcellproliferation,invasioningliomacells,suggestingapotentialbiomarkerforclinicalgliomatreatment[269].ThefolatecycleplaysakeyroleintheproductionofNADPHforneutralizationofROS.Circ_0062019anditshostgeneSLC19A1weresignificantlyupregulatedinprostatecancer.UpregulatedSLC19A1thusencodeamembraneproteintotransportfolate,whichdecreasesROSlevelsandpromotesprostatecancerproliferation[270].Therefore,theseabovefindingsdemonstratethattheinterplaybetweencircRNAsandoxidativestressplaysdominantroleinregulatingcancerhallmarks.AndmoretypesofncRNAswillbeidentifiedtointeractwithoxidativestressforregulatingcancerhallmarksinthefuture.ConclusionsTodate,mountingevidencehasdemonstratedthecriticalroleofROSintumorprogression,whichdisplayadouble-edgedfunctionbyactingeitherasasecondmessengerforsignaltransductionordamagingmacromolecules/organellesforcelldeath.Duringtheseprocesses,ROScanmodulatebiologicalfunctionbyregulatingseveralprotein-codinggenes(eitheronco-ortumorsuppressive)involvedinmosthallmarksofcancer,therebyregulatingcancerprogression.Inthisreview,wehighlightthatROSalsofunctionincellularbiologicaleventsbyinteractionwithnon-codingtranscripts,especiallymiRNAsandlncRNAs.Indeed,theinterplaybetweenROSandmiRNAs/lncRNAsistightlyassociatedwithdiversebiologicalprocesses,includingcancercellproliferation,cellsenescenceandcellinvasion,suggestingtheircrucialroleintheregulationofmostcancerhallmarks.Insummary,theinterplaybetweenncRNAsandROSholdsgreatpotentialforthedevelopmentofnoveldetectionbiomarkersortherapeuticstrategiesforfuturecancertreatment.ProspectiveTheinteractionbetweenncRNAsandROStakesplaceeitherduringncRNAbiogenesis,attheepigeneticlevelorduringthesignaltransduction.Inaddition,moststudiesindicatetheinterplaybetweenROSandncRNAsaremiRNAs-based.StudiesexploringtheassociationwithlncRNA/circRNAsandROSarestillrelativelylimited,althoughlncRNAandcircRNAmayplaymoreimportantrolesduringcancerprogression.AscircRNAsareabundant,conservedandstableinmammaliancells,theseadvantagesmakeitrelativelyeasytodetectandholdthepotentialtobeeffectivecancerbiomarkerinthefuture.Thus,thepossiblefutureresearchfocusesshouldpaymoreattentiontotheregulatoryroleofcircRNAincancer.Moreover,mostncRNAsstudiedtodateinteractwithROStoregulatecellgrowth-relatedcancerhallmarks,suchassustainingproliferativesignaling,evadinggrowthsuppression,andresistingcelldeath.However,onlylimiteddataexistsregardingregulationofevadingimmunedestructionofcancercells.Indeed,immunotherapyisnowoneofthemosteffectivetreatmentstrategiesforseveraltypesofcancer.ROSandncRNAsalonehavebeendemonstratedtoregulateimmuneescapeincancertreatment,butresearchesreferringtotheinterplaybetweenROSandncRNAsinimmuneescapearelimited.Furtherstudiesarethereforeneededfordeeperunderstandingtheirregulatoryrolesincancerimmuneescape.Additionally,studieshavefoundthatseveralncRNAsinteractwithROStoparticipateinregulationofmorethanonecancerhallmark.TakingmiR-21asanexample,itisabletoberegulatedbyorregulateROSgenerationincancercellsandmodulateseveralcancerhallmarks,includingsustainingproliferativesignaling,evadinggrowthsuppression,resistingcelldeath,inducingangiogenesis,tumor-promotinginflammation,andinvasionandmetastasis.ThismaybeanimportantissuewhichshouldbeaddressedwhentargetingtheinterplaybetweenncRNAsandROSforcancertherapyduetothecomplexinteractionpatternsanddiversemolecularmechanismsinvolved.ThepoorpharmacokineticsofncRNAsarealsoconsideredasanobstacleofncRNA-basedtargetedtherapy.Todate,mostofthestudiesrelatedtoncRNAsandROSareconductedininvitrocelllines,whichheralddelaysinthetimelineforimplicationofncRNA-basedtargetedtherapyincancertreatment.Nevertheless,withthetechnicaladvancementsincellularandmolecularbiologycoupledwithbioinformaticapproaches,almostcertainlymoreandmorencRNAswillbefoundtoworktogetherwithROStoregulatethehallmarksofcancer.Moreover,increaseduseofcanceranimalmodelsinfuturestudieswillpavethewayfortranslationofinvitroresultsintoclinicalapplications. Availabilityofdataandmaterials Allthedataobtainedand/oranalyzedduringthecurrentstudywereavailablefromthecorrespondingauthorsonreasonablerequest. AbbreviationslncRNA: longnoncodingRNA ncRNA: noncodingRNA ROS: Reactiveoxygenspecies H2O2 : Hydrogenperoxide miRNA: microRNA piRNA: PIWI-interactingRNA snoRNA: smallnucleolarRNA siRNA: smallinterferingRNA MREs: miRNAresponseelements lincRNA: intergeniclncRNA elncRNA: enhancerlncRNA GAS5: growtharrestspecific5 MALAT1: Lungadenocarcinomatranscript-1 circRNA: circularncRNA ceRNA: competitiveendogenousRNA ER: Endoplasmicreticulum PKM2: PyruvatekinaseM2 RTK: Receptortyrosinekinases CDK: Cyclin-dependentkinase CDKI: CDKinhibitor IR: Ionizingradiation ALA-SDT: 5-aminolevulinicacid-mediatedsonodynamictherapy MnSOD: Manganesesuperoxidedismutase HCC: Hepatocellularcarcinoma ASO: Antisenseoligonucleotide EGFR: Epidermalgrowthfactorreceptor Sp: Specificityprotein MAPK: Mitogen-activatedproteinkinases ESCC: Esophagealsquamouscellcarcinoma RB: Retinoblastoma FOXO: ForkheadboxO TNBC: Triple-negativebreastcancer PLC: Peptide-loadingcomplex HDACi: Histonedeacetylaseinhibitor UTR: Untranslatedregion BA: Betulinicacid POX: Prolineoxidase NEAT1: Nuclearenrichedabundanttranscript 1 EGCG: Epigallocatechin-3-gallate CTR1: Coppertransporter1 Bcl-2: B-celllymphoma2 PDCD4: Programmedcelldeath4 Keap1: Kelch-likeECH-associatedprotein1 ARE: Antioxidant-response-element EpRE: Electrophile-responseelement PRXL2A: Peroxiredoxin-like2A OSCC: Oralsquamouscellcarcinoma SCAL1: Smoke-andcancer-associatedlncRNA-1 TUG2: Taurine-upregulatedgene2 KRAL: Keap1regulation-associatedlncRNA CSC: Cancerstemcell GSC: Gliomastemcell TNBCSC: Triple-negativebreastcancerstemcell HAX-1: Hematopoieticcell-specificprotein1-associatedproteinX-1 OXPHOS: Oxidativephosphorylation PDAC: Pancreaticductaladenocarcinoma PFK1: Phosphofructokinase1 TCA: Tricarboxylicacid PDK2: Pyruvatedehydrogenasekinase2 PDH: Pyruvatedehydrogenase GLUT1: Glucosetransporter-1 HK2: Hexokinase2 PTBP1: Polypyrimidinetract-bindingprotein1 PPP: Pentosephosphatepathway G6PD: Glucose6-phosphatedehydrogenase PCGEM1: Prostatecancergeneexpressionmarker1 UCA1: Urothelialcarcinoma-associated1 FGF2: Fibroblastgrowthfactor2 VEGF: vascularendothelialgrowthfactor HIF: Hypoxiainduciblefactor HMOX1: Hemeoxygenase-1 PHD: Prolylhydroxylaseenzymes HRE: Hypoxiaresponseelement TXNIP: Thioredoxininteractingprotein ZEB2-AS1: ZincfingerE-box-bindinghomeobox 2antisenseRNA1 HIF2PUT: Hypoxia-induciblefactor-2αpromoterupstreamtranscript AP-1: Activatorprotein-1 TRAF3: Tumornecrosisfactorreceptorassociatedfactor3 EMT: Epithelial-mesenchymaltransition NRP1: Neuropilin-1 PICK1: ProteininteractionwithPRKCA1 HNSCC: Headandnecksquamouscellcarcinoma GSK3β: Glycogensynthasekinase-3beta MUF: Mesenchymalstemcell-upregulatedfactor SPARC: Secretedproteinacidicandrichincysteine TP53INP1: Tumorprotein53inducednuclearprotein1 ReferencesHanahanD,WeinbergRA.Hallmarksofcancer:thenextgeneration.Cell.2011;144(5):646–74.CAS  PubMed  GoogleScholar  Machado-SilvaA,PerrierS,BourdonJC.p53familymembersincancerdiagnosisandtreatment.SeminCancerBiol.2010;20(1):57–62.CAS  PubMed  GoogleScholar  DaytonTL,JacksT,VanderHeidenMG.PKM2,cancermetabolism,andtheroadahead.EMBORep.2016;17(12):1721–30.CAS  PubMed  PubMedCentral  GoogleScholar  GabayM,LiY,FelsherDW.MYCactivationisahallmarkofcancerinitiationandmaintenance.ColdSpringHarbPerspectMed.2014;4(6):a014241.PubMed  PubMedCentral  GoogleScholar  ShostakK,ChariotA.EGFRandNF-kappaB:partnersincancer.TrendsMolMed.2015;21(6):385–93.CAS  PubMed  GoogleScholar  SchieberM,ChandelNS.ROSfunctioninredoxsignalingandoxidativestress.CurrBiol.2014;24(10):R453–62.CAS  PubMed  PubMedCentral  GoogleScholar  FinkelT.Signaltransductionbyreactiveoxygenspecies.JCellBiol.2011;194(1):7–15.CAS  PubMed  PubMedCentral  GoogleScholar  ZhangJ,WangX,VikashV,YeQ,WuD,LiuY,etal.ROSandROS-mediatedcellularsignaling.OxidativeMedCellLongev.2016;2016:4350965. 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Consenttoparticipate Notapplicable. Codeavailability Notapplicable. FundingThisworkwassupportedbygrantsfromtheNationalNaturalScienceFoundationofChina(81821002,81790251and81672381),GuangdongBasicandAppliedBasicResearchFoundation(2019B030302012),theNational973BasicResearchProgramofChina(2013CB911300),andScienceandTechnologyDepartmentofSichuanProvince(no.2018RZ0133).AuthorinformationAuthornotesLiZhou,ZheZhangandZhaoHuangcontributedequallytothiswork.AffiliationsStateKeyLaboratoryofBiotherapyandCancerCenter,WestChinaHospital,andWestChinaSchoolofBasicSciences&ForensicMedicine,SichuanUniversity,andCollaborativeInnovationCenterforBiotherapy,Chengdu,610041,P.R.ChinaLiZhou, ZheZhang, ZhaoHuang & CanhuaHuangDepartmentofBiochemistryandMolecularBiology,MonashUniversity,Clayton,Victoria,3800,AustraliaEdouardNiceDepartmentofThoracicOncologyandDepartmentofRadiationOncology,CancerCenter,WestChinaHospital,SichuanUniversity,Chengdu,610041,P.R.ChinaBingwenZouSchoolofBasicMedicalSciences,ChengduUniversityofTraditionalChineseMedicine,Chengdu,611137,P.R.ChinaCanhuaHuangAuthorsLiZhouViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarZheZhangViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarZhaoHuangViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarEdouardNiceViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarBingwenZouViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCanhuaHuangViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarContributionsCHandBWZconceivedthestructureofmanuscript.LZ,ZZandZHdraftedinitialmanuscript.ECNrevisedthemanuscript.Allauthorsreadandapprovedthefinalmanuscript.CorrespondingauthorsCorrespondenceto BingwenZouorCanhuaHuang.Ethicsdeclarations Ethicsapprovalandconsenttoparticipate Notapplicable. 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ReprintsandPermissionsAboutthisarticleCitethisarticleZhou,L.,Zhang,Z.,Huang,Z.etal.Revisitingcancerhallmarks:insightsfromtheinterplaybetweenoxidativestressandnon-codingRNAs. MolBiomed1,4(2020).https://doi.org/10.1186/s43556-020-00004-1DownloadcitationReceived:11June2020Accepted:21July2020Published:31August2020DOI:https://doi.org/10.1186/s43556-020-00004-1SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative KeywordsncRNAsOxidativestressROSCancerhallmarks DownloadPDF Advertisement