An analysis of the role of HnRNP C dysregulation in cancers

Heterogeneous nuclear ribonucleoproteins C (HnRNP C) is part of the hnRNP family of RNA-binding proteins. The relationship between hnRNP C ... Skiptomaincontent Advertisement SearchallBMCarticles Search AnanalysisoftheroleofHnRNPCdysregulationincancers DownloadPDF DownloadPDF Review OpenAccess Published:08April2022 AnanalysisoftheroleofHnRNPCdysregulationincancers LiyiMo1,LijuanMeng2,ZhichengHuang1,LanYi1,NanyangYang1&GuoqingLi  ORCID:orcid.org/0000-0001-8169-04341  BiomarkerResearch volume 10,Article number: 19(2022) Citethisarticle 698Accesses 1Altmetric Metricsdetails AbstractHeterogeneousnuclearribonucleoproteinsC(HnRNPC)ispartofthehnRNPfamilyofRNA-bindingproteins.TherelationshipbetweenhnRNPCandcancershasbeenextensivelystudied,anddysregulationofhnRNPChasbeenfoundinmanycancers.Accordingtoexistingpublicdata,hnRNPCcouldpromotethematurationofnewheterogeneousnuclearRNAs(hnRNAs,alsoreferredtoaspre-mRNAs)intomRNAsandcouldstabilizemRNAs,controllingtheirtranslation.ThispaperreviewstheregulationanddysregulationofhnRNPCincancers.Itinteractswithsomecancergenesandotherbiologicalmolecules,suchasmicroRNAs(miRNAs),longnoncodingRNAs(lncRNAs),anddouble-strandedRNAs(dsRNAs).Evendirectlybindstothem.TheeffectsofhnRNPConbiologicalprocessessuchasalternativecleavageandpolyadenylation(APA)andN6-methyladenosine(m6A)modificationdifferamongcancers.Itsmainfunctionisregulatingstabilityandleveloftranslationofcancergenes,andthehnRNPCisregardedasacandidatebiomarkerandmightbevaluableforprognosisevaluation. IntroductionPost-transcriptionalprocessesarethemainmechanismsthatcontrolgeneexpressioninmammaliancells.RNA-bindingproteins(RBPs)isaclassofproteinsthatcanmediatepost-transcriptionalregulation.Inhumancells,RBPshavetheirRNA-bindingdomainsthatcaninteractwithRNAstoparticipateintranscriptionalprocesses[1].Heterogeneousnuclearribonucleoproteins(hnRNPs)arealargefamilyofRBPsthatarerichinthehumanbody.StudieshaverevealedthathnRNPscontainmorethan30proteins[2].HnRNPssharesomecommonfunctionsbecauseoftheircommonstructuralfeatures[3].TheseproteinscontainahighlyconservedRNA-bindingdomainattheiraminoterminus,andthecarboxylendhasauniquefunctionalregionthatcouldinteractwitheachoftheRBPs[4].Theyarefunctionallydiverseandcomplex.TheytakepartinthematurationofnewheterogeneousnuclearRNAs(hnRNAs,alsoreferredtoaspre-mRNAs)intomRNAsandcanalsostabilizemRNAs,controllingtheirtranslation[5].TheCproteintetramer,whichiscalledhnRNPCinthisarticle,wasidentifiedasacorecomponentofhnRNPparticlesthatformonallnascenttranscripts[6].Initsnaturalstate,itisatetramerthatincludes3C1proteins(41 kDa)and1C2protein(43 kDa)[7](Fig. 1A).Furthermore,ithasbeenproventhatC1andC2comefromasinglecodingsequence[8].HnRNPCislocatedinthecellnucleus[9,10],andbindswithpre-RNAtoformulatecomplexes,modulatingsplicingefficiency[11].Astudyin1986showedthatanhnRNPCantibodycalled4F4couldinhibitthesplicingofpre-mRNAandthat4F4canbeimmunoprecipitatedwitha60Ssplicingcomplex(spliceosome)thatcontainsaCprotein.Splicingofpre-mRNAwasnotinhibitedby4F4deactivatesorbytheuseofotherhnRNPproteinsantibodies[12].HnRNPCcouldstabilizemRNAandmodulatetheleveloftranslationbyinteractingwithpoly-Utractsofthe3′-uncodingregion(UTR)or5′-UTRofmRNA[13,14].Inaddition,hnRNPCisanimportantN6-methyladenosine(m6A)reader.Thebindingofthesecomponentscouldbefacilitatedbythe‘m6A-switch’mechanism[15].Fig.1StructureofhnRNPC.ATetrahedralstructureofhnRNPCinelectronmicroscope.BTheaminoacidsequenceofhnRNPC1,theredpartisthe13aadifferentfromhnRNPC2.13aa:13animoacids.CFunctionalmotifsofhnRNPC1andC2.RRM:RNArecognitionmotif;bZLM:Basicleucinezipper-likemotif;NLS:Nuclearlocalizationsignal;CLZ:Leucinezipper-likeoligomerdomain;CTD:C-terminaldomainFullsizeimageStudiesonthefunctionofhnRNPCindicatethatitisnecessaryattheorganismlevelbutnotatthecelllevel.KnockingouthnRNPCinmicearrestsdevelopmentattheeggcylinderstage[16].HnRNPCknockoutinmurinestemcellsonlyresultedinalowdifferentiationrate,1andyeast,anothereukaryote,alsolacksthisgene[17].ThismeansthathnRNPC1/C2mayinfluencetherateand/orfidelityofoneormorebiologicalprocesses.Indeed,manystudiesilluminatehnRNPCandplaykeyrolesinmanyhumandiseases.ItisnotclearwhatkindofsystemicrolehnRNPCplaysinhumansandhowitisrelatedtohumandisease.Herein,wereviewedthefunctionsofhnRNPCincancers.StructureHnRNPCexhibitsauniquesupramolecularassembly;itiscomposedoffoursubunits:3C1subunitsand1C2subunit[18](Fig.1A).In1995,imagesofhnRNPCfromdifferentdirectionswereobtainedusinganelectronmicroscope[19].Approximately50%oftheimagesshowedthatthesefoursubunitsformaplanequadrilateral.However,atrianglethree-subunitstructurewasalsoshownintheimages.Inaddition,hnRNPChasastablestructureinnature.AlloftheseresultsillustratethatthemacroscopicstructureofhnRNPCmostlikelyinvolvedatetrahedralconfiguration(Fig.1A).IsoformC2contains306aminoacids(aa).IsoformC1differsfromC2inthatitismissing13aainthe108–120aaregion[20];thetotalaminoacidsequenceisshowninFig.1B.IntheN-terminus(Fig.1C),locatedinthe16–87aaregion,theRNArecognitionmotif(RRM)isanRNA-bindingdomain(RBD)thatis72aainlength[21].Structurally,theRRMconsistsoffourβ-sheetsandtwoα-helices(βαββαβ).ItcontainsconservedRNP1octamericandRNP2hexamericsequences,andtheyare30aminoacidsapart[22].Thevariableloopsconnectingtheβ-sheetscontributetotheRNA-bindingspecificityofhnRNPC[23].RRMhasfivebindingpockets,andtheycanrecognizeuridineswithanunusual5-to-3baseselectivitygradient.Moreover,fivesuccessivefragmentsofUresidueswerescreened,andbindinganalysisshowedthatthissequenceconstitutedthebindingsitewithhighaffinity(Kd = 170 nM)forhnRNPC1.Ithasbeenconfirmedthatfull-lengthhnRNPCtendstobindwithsequencesthatarerichin“U”[24].The155–161aasequenceisanuclearlocalizationsignal(NLS)(Fig.1C),whichistypicallyashortpeptidesequenceresponsibleforthenuclearentryofnucleophilicproteins.Typically,thesesequencescontain4 ~ 8aminoacids,andtheclassicalNLSconsistsofone(one-part)ortwo(two-part)basicaminoacidchains.ThisresultisinlinewiththeprinciplethatthisNLSsequenceisPro-Ser-Lys-Arg-Cln-Arg-Vla[25,26,27].Residues140–214constituteaparticulardomaincalledthebasicleucinezipper-likemotif(bZLM)(Fig.1C).ThefunctionsofhnRNPC,suchasstabilizingpre-RNAandmediatingsplicing,aredependentontheRRMandbZLM.Additionally,bZLMisamajordeterminantofhnRNPC’shigh-affinityinteractionwithRNA,oligomerizationanditshighlysynergisticRNAbindingactivity[17].IntheC-terminusofthebZLM,thereisa28-aahelicalregion(residues180–207),whichiscalledtheleucinezipper-likeoligomerdomain(CLZ)(Fig.1C).TheCLZdomainofC2andC2itselfarethebindingpartnersofhnRNPC,andthreeC1particlesactasthereceptors[24].ItshouldbenotedthatthespecificityofRNAbindingislargelymediatedbythe3Dstructureoftheprotein,inwhichstructuralregionsaroundtheRNA-bindingdomainfine-tunetheinteractionsofRNAproteins.TheCLZisoneofthesestructuralregions.Likemanychargedproteins,hnRNPC1andC2usealpha-helicesasanoligomerizationmechanismandarepartiallystabilizedbycontinuoushelixcontactsformedbetweenamphiphilichelixhydrophobicsurfaces,andforeachsetofsevenresiduesalongthehelixasacyclicunit[28],a230-nt(nucleotide)regionofRNAcouldhavefouridenticalcontactswiththeRRM.C1andC2monomershaveonlyoneRBD,andtheyhavetooligomerizewitheachothertoformspecificandpowerfulRNAinteractions.ThispolymerizationcapacityismediatedbytheCLZdomain[29].ThissynergisticinteractionbetweenthesefourparticlesofhnRNPCisnecessarytoformhnRNPCtetramerstomeasurethelengthofnewlyformedtranscripts[30].Moreover,mutationoftheCLZdomaininhnRNPCproteinsresultsinlow-affinitybindingtopre-RNA[31].TheRNAsitesizeofasingleCproteintetrameris230to240 nt,andthreetetramers,hnRNPA,BandC,couldconstituteaunique19Striangularcomplexthatfoldsasingleparticlelengthofpre-RNA(700 nt).TheformationofthehnRNPCtriangularcomplexisaprimaryeventfortheassemblyofother40ShnRNPcoreparticlesinvitroandinvivo[32].AttheendoftheC-terminusofhnRNPC,thereisadomaincalledtheC-terminaldomain(CTD,residues208–290)(Fig.1C).ItisworthmentioningthatthisdomainhasfourphosphorylationsitesthatcouldparticipateinphosphorylationanddephosphorylationofhnRNPC,andstudieshaveshownthatdephosphorylationofhnRNPCproteinsisnecessaryfortheirbindingtosomepre-RNAs[33,34,35].ThesediscoverieshighlightthatCTDphosphorylationanddephosphorylationareimportantforpre-spliceosomeassembly.Becauseofthesefunctionalstructures,hnRNPCisabletobindtocertainbiomoleculesandperformitsfunctionsinbiologicalprocesses.RoleofhnRNPCdysregulationincancersHighexpressionofhnRNPChasbeenfoundinmanykindsofcancers,andupregulationofhnRNPCalwaysindicatesapoorerprognosis;thishasbeendemonstratedincancerssuchasbreastcancer[36],glioblastomamultiforme(GBM)[37],andgastriccancer[38].Therefore,hnRNPCisregardedasacandidatebiomarkerandmightbevaluableforprognosisevaluation.Inglioma,theupregulationofhnRNPCisrelatedtoahighdegreeofmalignancy,andclinicalresearchhasshownthattheupregulationofhnRNPCmightbeassociatedwithagoodprognosisforgliomapatients[37].AnotherKaplan–Meiersurvivalanalysisfromnon-small-celllungcancer(NSCLC)showedthatpatientswiththehigherhnRNPCexpressionlevelswerepredictedtohaveshortersurvivaltimesandtohaveaworseprognosis[39].Italsoshowednosignificanceinsomesituations,suchasastudyforcolorectalcancer[40].butastudyformetastaticcoloncancercellsshowedthatoverexpressionofhnRNPCplaysacriticalroleinthealternativecleavageandpolyadenylation(APA)profile,whichhasbeenlinkedtocancerprogression[41].TheoverviewoftheglobalfunctionsofhnRNPCdysregulationincancer(Table 1)showsthathnRNPCisanegativeelementforcancertreatment.However,itisnotclearhowitexertstheseeffectsandwhatroleitplays.Next,wewillexplainhowitactsondifferentbiomolecules(Fig. 2)andwhatregulatesitsexpressionincancer.Table1RoleofhnRNPCregulationanddysregulationincancersFullsizetableFig.2HnRNPCinteractswithothermoleculesincancercells.dsRNA:double-strandRNA.RIG-I:retinoicacid-induciblegeneI.IFN-α:typeIinterferonα.JAK:JanusKinase.STAT1:signaltransducerandactivatoroftranscription1.KHSRP:KHtype-splicingregulatoryprotein.ARAD:Adenosinedeaminase,RNAspecificFullsizeimageHnRNPCandproteinsP53actsasatumoursuppressorinmanytumourtypes[47].HnRNPCwasalsodiscoveredtointeractwithp53bydirectlybindingtop53andcouldmakep53unstable,preventitsactivation,anddownregulateitsproteinlevel[48].Moreover,ithasbeenfoundthatRNAcannegativelyregulatethehnRNPC-p53interaction.TheexpressionlevelsofhnRNPCandKHtype-splicingregulatoryprotein(KHSRP)inNSCLCtissuesweresignificantlyhigherthanthoseinparacancerousnoncanceroustissues;KHSRPisalsoapre-mRNAsplicingprotein.IncreasedexpressionofhnRNPCwasfoundtobesignificantlyassociatedwithadvancedtumourstageandmetastasisTheoverexpressionofhnRNPCsignificantlypromotedtheproliferation,migrationandinvasionoflungcancercellsinvitroandinvivo.WesternblottingrevealedthathnRNPCisadownstreamproteinofKHSRPandmayinducetheinvasionandmetastasisofhumanlungcancercellsthroughactivationoftheIFN-α-JAK-STAT1signallingpathway(Fig.2)[39].HnRNPCandmicroRNAs(miRNAs)MiRNAsareakindofnoncodingRNAwithalengthofapproximately22 nt.TheyareimportantendogenousRNAsthatcanregulategeneexpressionandarepromisingcandidatesforbiomarkerdevelopment[42].AstudyofGBMshowedthathnRNPCcouldbinddirectlytoprimarymiRNAandpromotemiRNAexpressioninT98Gcells.WhenhnRNPCissilenced,miR-21isexpressedatlowerlevels,andprogrammedcelldeath4(PDCD4),whichisthetargetgeneofmiR-21,isupregulated[49].ThiseffectonmiR-21maybeduetotheRNAsplicingfunctionofhnRNPC,whichinturninhibitsthemigrationandinvasionofT98Gcells.Indeed,theupregulationofhnRNPCinhighlyaggressiveU87MGcellsalsosupportedthepotentialvalueofhnRNPCasaprognosticandtherapeuticmarkerforGBM[43].ThisexampleshowsthathnRNPCcanactonmiRNAsandthathnRNPCandmiRNAscaninteractwitheachother.MiR-744-5pbindstohnRNPC,andhnRNPCinfluencesthemiR-21expressionlevel.MiR-744-5pcouldleadtothedownregulationofBcl2levels,whichhaspro-apoptoticeffectsinovarianserouscystadenocarcinoma[44].MDA-MB-435-LvBr2(LvBr2)isakindofBrain-trophicmetastaticcell,hnRNPChasahighexpressiveinit,andvirtually,miR-146aabsencefrombrainmetastases.miR-146ainLvBr2cellscouldinteractwithhnRNPC,promotingthemigrationandinvasionofLVBR2cells[50].Therefore,inhumancancercells,miRNAsdownregulatehnRNPCexpression.Perhapsthisisamechanismofcancergrowthandmetastasis.Moreover,hnRNPCshortensUTRsinmRNAAPAisoforms.ThisshorteningmayimprovethetranslationaloutputofkeygenessuchascellcycleregulatorsbyavoidingexposuretosuppressormodulessuchasmiRNAs[51].Overall,hnRNPCdirectlybindsandshortensUTRs,promotingtheexpressionofmiRNAsandthusinfluencingothercancer-relatedgenes.HnRNPCandlncRNAsLongnoncodingRNAs(lncRNAs)areRNAsconsistingofmorethan200 nt[52],andmanylncRNAsconsideredhighlyconnectedwithcancer.Protein-lncRNAinteractionsplaykeyrolesinmanycellularprocesses,suchassplicing,polyadenylation,transport,stabilityandtranslation[45].Onestudyshowedthatm6AcouldchangethelocalstructureofmRNAandlncRNA,promotinghnRNPCbinding[15].LncRNASNHG1isretainedinthenucleusbynucleolarbindingandbindstop53-competinghnRNPC,whichpromotesp53-dependentapoptosisbydisruptingtheregulationofp53activitybyhnRNPCandupregulatingp53levels[48].LBX2-AS1isalncRNAthatishighlyexpressedinoesophagealsquamouscellcarcinoma(ESCC)samples.ThroughinteractingwithhnRNPC,LBX2-AS1couldenhancethestabilityofzincfingerE-boxbindingprotein1(ZEB1)andzincfingerE-boxbindingprotein2(ZEB2)mRNAs,whicharethemostcriticalepithelial-mesenchymaltransition(EMT)conversionmolecules,promotingESCCcellmigration[46],anditalsoconfirmedknockdownofhnRNPCcouldsuppresscellmigrationandreversedEMTprogress.Similarly,LINC00662,whichisoverexpressedinoralsquamouscellcarcinoma(OSCC),recruitedhnRNPCproteintoincreaseAK4expression.AndAK4hasbeendemonstratedasacarcinogen.ItreducestheradiosensitivityofOSCCcells[53].TheselncRNAscaneffectivelyinhibitthebindingofhnRNPC,whichmayexplainwhyhnRNPCishighlyexpressedincarcinomas.ManycancershavebeendemonstratedtoexhibitoverexpressionofhnRNPC.ItispossiblethatPossiblyhnRNPCisadownstreammoleculeoflncRNA.HnRNPCandAluelementsInthebreastcancercelllinesMCF7andT47D,hnRNPCrepressioninhibitedcellproliferationandtumourgrowth,andthesupernatantfromhnRNPCknockdowncellsinhibitedbreastcancergrowth[36].TherepressionofhnRNPCinducedtheupregulationofendogenousdouble-strandedRNA(dsRNA),whichisnonviralandknownasoneofthebindingligandsofretinoicacid-induciblegeneI(RIG-I)(genenameDDX58)[54].However,inothertumourcelllines(MDA-MB-231andBT549)ornon-tumourMCF10Acells,hnRNPCknockoutdidnotinduceinterferon(IFN)responseordsRNAaccumulationintheseunresponsivecells[36].ThissuggeststhattheremaybeacomplementarymechanismthathelpsretaincontroloftheIFNresponseanddsRNAaccumulationbycompensatingfortheabsenceofhnRNPCinthesecells.ThisdiscoveryofdsRNAinhibitionbyhnRNPCisanovelextensionofthepreviouslycharacterizedfunctionofhnRNPC,whichbindstopre-mRNAintronsandregulatesRNAsplicing.EndogenousdsRNAcantriggertheIFNresponse[55].Thisworkissointerestingthatsomescientistspublishedacomment[56].IFNinjectionhasbeenatreatmentsincethe1970s[57].TheactivationofIFNbyendogenousretroviraldsRNAwasobservedinhypomethylatedtesticulargermcelltumours,andtheexpressionofIFNwasonlylimitedinneoplasticseminomacells[58].Inbreastcancer,endogenousnucleicacidandhnRNPCpromoteIFNproductionincancercells,indicatingthatdsRNAcouldatleastberegulatedbythehnRNPC/dsRNAaxis.Moreover,theintermediatetransmitterdsRNAistrulyendogenous.Itisacomplementarymechanismproductinsteadofaretroviralproduct.Thatis,IFNcouldbeinfluencedbyexternalfactorsandintracellularnucleicacids.PerhapsthisfindingcouldexplainthedifferenceintheeffectivenessofIFNtherapies.Theseup-regulateddsRNAspeciesarerichintheAlusequences,whichwereknownforharbouringhnRNPCbindingsites.ItcouldbeconsideredthattheinteractionbetweenhnRNPCanddsRNAcanbeseenasapartoftheinteractionbetweenhnRNPCandAlu.TheAluelementisamajortargetoftheRNAeditingenzymeadenosinedeaminase,RNAspecific(ADAR)[59].Aluelementscanactassplicingreceptors,inhibitmRNAtranslationandcausegeneticinstability.HnRNPCcanpreventsomesplicingfactors(suchasU2AF65)frombindingtoAluelementstoprotectagainst“Aluexonization”sothatAluelementsarenotatriskofabnormalincorporationintomaturetranscripts[60].ThisphenomenonindicatesthathnRNPChasafunctioninmaintainingtranscriptomestability.However,itisunclearhowhnRNPCprotectsagainst“Aluexonization”.KnockdownofhnRNPCresultsintheseparationofthetwoarmexonsoftheAluelementandalmostcompleteskippingofupstreamreplacementexons.ResearchhasfoundthatcompetitionbetweenhnRNPCandU2AF65preventsthetranscriptomefromfacilitatingtheexonizationofAluelements[60].DeletionofhnRNPCleadstotheformationofpreviouslysuppressedAluexons,whichseverelydisruptstranscriptionalfunction.TheinhibitionofhnRNPCisAludependent[61].U-bundlemutationofAluelementsmitigateshnRNPCinhibition,resultinginstronginclusionofAluexonsandskippingreplacementexons.Incontrast,inthehnRNPCknockdownprocess,thecompleteremovaloftheAluelementeliminatesanyregulationoftheupstreamoptionalexon.TheseobservationsareconsistentwiththemodelofdynamicprocessingcompetitionbetweenAluexonsandupstreamreplacementexons,andthesamephenomenonoccurswithinthegeneanddownstreamregions[61].ItplaysakeyroleinfacilitatingthetherapeuticeffectsofantitumourdrugssuchasDNAmethyltransferaseinhibitorsandCDK4/6inhibitorsonmanykindsofcancers[62,63].HnRNPCandAPAeventsWestilldonotknowthemechanismbywhichhnRNPCpromotesmiRNAexpressionandthenchangesthecellphenotype.APAaregeneralmechanismsofmammaliantranscriptionaldiversificationandhaverecentlybeenassociatedwithproliferativestatusandcancer[64,65].Betweennormalandcancercells,themostprominentAPAprofilechangeshavebeenfound,andcancercellstendtoexpressmRNAAPAisoforms[51].APAfacilitatestheinclusionorexclusionofthesesites(RBPsitesandmiRNAtargetsites),providinganopportunityforcellstoregulategeneexpressionattheposttranscriptionallevelbyaffectingtranscriptionalstability,translationoutput,andsubcellularlocalization[66].3′-UTRtruncationofgrowth-promotingmRNAtranscriptsalleviatesinhibitionmediatedbyintrinsicmiRNAsandAu-richelementstopromotefacilitativetranslationofkeygenes[65].Forexample,theexpressionofshortermRNAsubtypesoftheproto-oncogeneIGF2BP1/IMP-1resultedinmoreoncogenictransformationsthantheexpressionoffull-lengthannotatedmRNAs[50].Inaddition,thisisrelatedtotheimmunemicroenvironmentinpancreaticadenocarcinoma[67].Inaddition,elevatedlevelsofhnRNPCinmetastaticcoloncancercellsdrivecodingregion(CR)andUTRAPAofagroupofgenes,includingmethylenetetrahydrofolatedehydrogenase(NADP+-dependent)1-like(MTHFD1L),andthesechangesarecloselyassociatedwithcancerprogression[41].KnockdownofhnRNPCcanlengthenUTR-APA,whichisshorterincolorectalcarcinomacellsthaninnormalcells[41].MihaelaZavolan’sstudyshowedthatthefrequencyofhnRNPCbindingtopoly(U)bundlespeaksnearthepoly(A)sites,andtheapparenteffectofhnRNPCbindingsitesonregulatingpolyadenylationdecreasedwithincreasingdistancefrompoly(A)sites[68].IthasbeenreportedthatmRNAAPAisoformswithshorterUTRstendtobeexpressedincancercells[69].Thismaybeaccomplishedbycontrollingpoly(A)siteselectionthroughhnRNPCtoupregulatetheproductionoffull-lengthMTHFD1LmRNA.ThisinferenceisconsistentwiththeobservationthatknockdownofhnRNPCcanlengthenUTR-APAincoloncancercells[41].Importantly,hnRNPCcouldhidepoly(A)sitesthroughthetightbindingofhnRNPCtothethree-terminalprocessingsitestoobscuretheircleavageandpolyadenylation.BoththenumberandlengthofuridinebundlescontributetotheuseofhnRNPC-dependentaggregation(A)sites.ThedownregulationofhnRNPCdecreasedwithincreasingdistancebetweenthepoly(A)sitesandhnRNPCbindingsites[68].WhenhnRNPCwasknockeddown,theuseofintronpoly(A)sitesincreased,whichcannotbeexplainedbyalternativesplicingevents.WhenhnRNPCwasknockedout,theincidenceofintronsitecleavageandpolyadenylationalsoincreased.However,intheterminalexon,theU-richpoly(A)sitesusedduringhnRNPCknockouttendtobedistallylocated.Inthesetranscripts,hnRNPCmayplaytheroleof“blocking”the“stronger”signalatthedistalend,allowingtheuseofthe“weaker”proximalpoly(A)site[70].Theyalsofoundthattheintronaggregation(A)siteismostlikelytobedeleted,whichshortensthelengthoftranscripts.ThisishowhnRNPCregulatesAPAevents.Itisworthmentioningthatthe3′-UTRsregulatedbyhnRNPCarerichinELAV-likeRBP1(ELAVL1)bindingsites,includingCD47genebindingsitesinvolvedintherecentlydiscovered3′-UTR-dependentproteinlocalizationmechanism(UDPL).Indeed,hnRNPCknockoutpromotestheexpressionofthelongCD473′-UTR[70].Thisconfirmsthat3′-UTR-dependentproteinsarehnRNPCresponsetranscripts.CD47proteinisahottumourtarget.ThisalsoconfirmstheimportanceofhnRNPCincancerresearch.HnRNPCandm6AHnRNPCisoneofthem6AmethylationRNAregulators(“readers”)[15].HnRNPCcouldaltermRNAandlncRNAinanm6A-dependentmanner.M6A-relatedbioinformaticsanalysisrevealedthatoverexpressionofhnRNPCfacilitatestheprogressionofOSCCviaEMT[71].Italsohasmultipleotherfunctions,suchasincreasingdifferentiationintypeIItesticulargermcelltumours(TGCTs)[72],inducingcelldeathinovariancancer,promotingchemotherapyresistance,indicatingoverallsurvival(OS)ingastriccancer,andpromotingtheprogressionofcolorectalcancer.Italsoshowedvalueindiagnosis,progressionandprognosisevaluationinlungadenocarcinoma,oesophagealcancer,adrenocorticalcarcinoma[73],urothelialcarcinomaofthebladder[74],andkidneyrenalpapillarycellcarcinoma[75,76,77].HnRNPCissignificantlyrelatedtotheOSofmanykindsofcancers,suchaspancreaticcancer[78],soitisaneffectiveprognosticmarker.LncRNAmetastasis-associatedlungadenocarcinomatranscript 1(MALAT1),whichhasanm6Asite,wasrecentlyshowntoinducelocalstructuralchangesthatincreasetherecognitionoftheU5channelandarerecognizedandboundbyhnRNPC[79].Inaddition,asanm6Aregulator,hnRNPCgivesrisetoamalignantphenotypeinpancreaticductaladenocarcinoma(PDAC)cellsbyantagonizingTAF8L(antimetastaticisoform)andincreasingTAF8S(prometastaticalternativesplicingisoform).Whenanm6AmutationoccursinTAF8,theinteractionbetweenhnRNPCandtheTAF8transcriptweakens,andTAF8Sexpressiondecreases[80].ThisindicatesthattheinteractionbetweenhnRNPCandm6AmediatesshearingeventsthataffectPDAC.ThebindingactivityofhnRNPCregulatedbythem6AswitchaffectstheabundanceandselectivesplicingoftargetRNAs.RBPsregulateRBMpathwaysthroughm6A-dependentRNAstructuralremodellingandprovideanewdirectionforthestudyofepigeneticsbyRNAmodification.Conclusions/expectationsInrecentyears,hnRNPChasbeenseenasapromisingbiomarkerindifferentkindsofcancers,asaprognosticmarkerforcancer[81].Itinfluencesmanybiologicalmoleculestoexertitseffects.Inmostofthosestudiesmentioned,elevatedhnRNPCusuallyindicatesapoorprognosis.However,inafewcases,hnRNPCdoesnotshowanysignificance[82].Thiscouldexplainwhythereisnoperfectbiomarkertoestimatetheprognosisofcancerpatients.Ithasbeenproventohavevalueinmostcases,sowecouldsayithasthepotentialtobeusedintheclinic.However,withthisoptimisticperspective,contradictingresultsshouldalsobenoted.AstudyonGBMfoundthathnRNPCwaspositivelycorrelatedwithmalignancy,butwhenassessingtheOStimeofpatientswithhighexpressionandlowexpression,hnRNPCwasnegativelycorrelatedwithprognosis[37].Inotherresearch,highexpressionofhnRNPCindicatedapoorprognosis[71].Asusual,thehigherthedegreeofmalignancywas,theworsetheprognosisofthepatients.Thisdoesnotseemtobeduetosamplingerror.AnotherstudyonGBMfoundthathnRNPCpromotesmigrationandinvasion.Overall,moredataontheeffectofhnRNPConOStimewouldhelpsupporttheseconclusions.GiventhathnRNPCislocatedinthenucleus[83],itmaynothaveanadvantageasaclinicaltumourmarker.LikelivercancerbiomarkerAFP,aclinicalbiomarkershouldhavehighspecificityandsensitivityandisalsodetectableduetoitsperipheraldistribution.However,hnRNPCdoesnothavethesefeatures.Inthefuture,itisimportanttofocusonmethodsfortargetinghnRNPCtotreatcancer.Inadditiontoitsroleincancer,hnRNPCplaysanimportantroleinotherhumandiseases.Inthenervoussystem,hnRNPCbindswitha29-ntsequenceinthe3′-UTRofamyloidprecursorprotein(APP)mRNA,whosecleavageproductAβishighlycorrelatedwithdegenerativeneuropathy,suchasAlzheimer’sdisease,andregulatesneuronalsynapsegrowth[84,85,86,87,88].TheseresultsproveditseffectsinstabilizingandenhancingthetranslationofmRNA.Inaddition,hnRNPCplaysanimportantroleinspinalmuscularatrophy(SMA)andviraldiseasessuchashepatitisBvirus(HBV).Inaddition,hnRNPCparticipatesinageingandregeneration.Itcaninteractwiththehumantelomeraseholoenzymeandisrelatedtotheabilityoftelomerasetoaccesstelomeres[89].Afterall,themaintenanceoftelomerelengthmayindicatecancersinsteadoflongerlifespan[90].Inacutepromyelocyticleukaemia(APL),anovelnewfusionbetweentheHNRNPCgeneandtheRARGgenehasbeenfound[91].OnethinghasbeenverifiedthatHNRNPC-RARAisaregulargeneticeventinsteadofarandomoneanditisarefractorycase.Indeed,hnRNPCplaysanimportantroleinmanytranscription-relatedeventsandmaintainsthestabilityofmRNAinnormalcells.Basedontheabovefindings,itislikelythatthedysregulationofhnRNPCisanegativefactorforhumanhealth.Insummary,asanRBP,hnRNPCbindswithmiRNA,promotingitsexpression.HnRNPCcouldbindlncRNAs,alteringtheireffectsonothermolecules.HnRNPCcouldinteractwithAluelementstopreventdsRNAfromstimulatingtheimmuneresponse.Inaddition,itcouldinteractwithothergenes,suchasP53,toexertitseffects.Italsoplaysasplicingfunction,regulatingAPAeventsandm6Aevents,thusaffectingthetumourprocess. 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AbbreviationsAcute: promyelocyticleukaemia APL: Alternativecleavageandpolyadenylation APA: Aminoacids aa: Amyloidprecursorprotein APP: Adenosinedeaminase,RNAspecific ADAR: Basicleucinezipper-likemotif bZLM: C-terminaldomain CTD: Codingregion CR: Double-strandedRNAs dsRNAs: ErogeneousnuclearribonucleoproteinsC hnRNPC: HeterogeneousnuclearRNAs hnRNAs: HepatitisBvirus HBV: Interferon IFN: KHtype-splicingregulatoryprotein KHSRP: Leucinezipper-likeoligomerdomain CLZ: LongnoncodingRNAs lncRNAs: MicroRNAs miRNAs: Methylenetetrahydrofolatedehydrogenase1-like MTHFD1: Metastasis-associatedlungadenocarcinomatranscript 1 MALAT1: Nuclearlocalizationsignal NLS: Non-small-celllungcancer NSCLC: Oesophagealsquamouscellcarcinoma ESCC: Oralsquamouscellcarcinoma OSCC: Overallsurvival OS: Pancreaticductaladenocarcinoma PDAC: RNA-bindingproteins RBPs: RNArecognitionmotif RRM: RNA-bindingdomain RBD: Retinoicacid-induciblegeneI RIG-I: Spinalmuscularatrophy SMA: Testiculargermcelltumours TGCTs: Uncodingregion 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DownloadreferencesAcknowledgementsThisworkwassupportedbyHunanNaturalScienceFoundation(No.2020JJ4530),theResearchInitiationFundingoftheUniversityofSouthChinaforDoctors(No.2018XQD09),ScienceandTechnologyFoundationofHengyang(No.2020-67-9,2020jh042697)andUniversityStudentsStudyandInnovationPilotProject(No.2020-191-2792).FundingThisworkwassupportedbyHunanNaturalScienceFoundation(No.2020JJ4530),theResearchInitiationFundingofUniversityofSouthChinaforDoctors(No.2018XQD09),ScienceandTechnologyFoundationofHengyang(No.2020-67-9,2020jh042697)andUniversityStudentsStudyandInnovationPilotProject(No.2020–191-2792).AuthorinformationAuthorsandAffiliationsTheHengyangKeyLaboratoryofCellularStressBiology,InstituteofCytologyandGenetics,HengyangMedicalSchool,UniversityofSouthChina,Hengyang,421001,Hunan,ChinaLiyiMo, ZhichengHuang, LanYi, NanyangYang & GuoqingLiDepartmentofUltrasonography,SecondAffiliatedHospital,UniversityofSouthChina,Hengyang,421001,Hunan,ChinaLijuanMengAuthorsLiyiMoViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarLijuanMengViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarZhichengHuangViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarLanYiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarNanyangYangViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarGuoqingLiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarContributionsGuoqingLi,NanyangYang,LiyiModraftedthemanuscriptandfinalizeditwithinputfromLijuanMeng,ZhichengHuangandLanYi.Allauthorsapprovedthefinalmanuscript.CorrespondingauthorsCorrespondenceto NanyangYangorGuoqingLi.Ethicsdeclarations Ethicsapprovalandconsenttoparticipate Notapplicable. 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ReprintsandPermissionsAboutthisarticleCitethisarticleMo,L.,Meng,L.,Huang,Z.etal.AnanalysisoftheroleofHnRNPCdysregulationincancers. BiomarkRes10,19(2022).https://doi.org/10.1186/s40364-022-00366-4DownloadcitationReceived:03January2022Accepted:20March2022Published:08April2022DOI:https://doi.org/10.1186/s40364-022-00366-4SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative KeywordsRNA-bindingproteinHnRNPCCancersMolecularinteractions DownloadPDF Advertisement BiomarkerResearch ISSN:2050-7771 Contactus Submissionenquiries:[email protected] Generalenquiries:[email protected]