癌基因与抑癌基因课件

OncologyLectureSeriesOncogenesandTumorSuppressorGenesOncologyLectureSeriesOncogenOverviewCancerandCancerGenomicsOncogenesandTumorSuppressorGenesClinicalImplicationsofCancerGenes123OverviewCancerandCancerGenoCancerandCancerGenomics1CancerandCancerGenomics190%Sporadiccancer10%Familialcancer,BRCA1/2CancerarisesfromgeneticandepigeneticalterationsinnormalcellulargenesMorethan200typesofcancerCancerisadiseaseofthegenomeVogelsteinB,etalScience2013BreakthroughExpansionInvasive90%SporadiccancerCancerarCarcinomas-cancersthatstartintheepithelialtissuessuchasskinortissuesthatlineorcoverinternalorgansSarcomas-cancerthatbeginsintheconnectiveorsupportivetissuessuchasbone,muscleorbloodvesselsLeukemia-cancerthatstartsinthebloodformingtissuesuchasbonemarrowLymphomaandMyeloma-cancersthatbegininthecellsoftheimmunesystemBrainandSpinalCordCancers-derivedfromcentralnervoussystemcancersMainCategoriesofCancerMainCategoriesofCancerCancerisComplexThehallmarksofcancer:thenextgeneration,Hannahan&Weinberg,Cell2011Metabolicdisease,Immunedisease,Environmentaldisease1.Sustainingproliferativesignaling2.Lossofgrowthsuppressors3.Apoptosisresistance4.Infiniteproliferativecapacity5.Angiogenicpotential6.InvasionandmetastasisSixMajorPathwaystocancer:CancergenomesCancerisComplexThehallmarksToobtaina

comprehensivedescriptionof

genomic,transcriptomicandepigenomicchanges

in

50differenttumortypesand/orsubtypes

whichareofclinicalandsocietalimportanceacrosstheglobe.(25000patients)Timeline:2010-Team:GlobalinstitutionsTogeneratecomprehensivedatasettodescribethemolecularchangesin33differenttumortypesfrom11000patientsTimeline:2005-2016Team:20collaboratinginstitutionsinUSandCanadaCancerGenomeProjectsToobtaina

comprehensivedescInternationalCancerGenomicStudiesDifferencein: EthnicityDietaryHabitsCarcinogen(eg.,betalnuts,AA)Pathogen(eg.,HPV,EBV,liverfluke)EnvironmentandPollutionInternationalCancerGenomicSHelicobacterpyloriGastricCancerOpisthorchisviverrini(LiverFluke)BileDuctCancer(Cholangiocarcinoma)AristolochiaPlants(egBirthwort)UrinaryTractCancerEpstein-BarrVirusNasopharyngealCancerPathogenandCarcinogensinAsianCancersHelicobacterGastricCancerOpisLBAlexandrovetal.Nature000,1-7(2013)doi:10.1038/nature12477TheprevalenceofsomaticmutationsacrosshumancancertypesMutationallandscapesfromwhole-genomesequencingof3281cancergenomesfrom12maincancertypesLBAlexandrovetal.Nature00SnapshotofCancerGenomicLandscape1AnOetalDatabase.doi:10.1093/database/2015.

2VogelsteinBetal.Science.2013;339(6127):1546-1558.SnapshotofCancerGenomicLan0-2drivermutationsinpediatrictumors3-6driversmutations(occasionally1-2)incommonadultNumberofdrivermutationspertumorVogelsteinB,etalScience20130-2drivermutationsinpediatCKandoth

etal.Nature502,333-339(2013)doi:10.1038/nature12634The127significantmutatedcancergenesidentifiedin12cancertypes.KRASPIK3CAPTENVHLAPCTP53OncogeneTumorsuppressorgenesEGFRRTK/RAS-PI3KsignalingCKandothetal.Nature502,3OncogenesandTumorSuppressorGenes2OncogenesandTumorSuppressorConcept:Oncogenes:

Genesencodingproteinsthatpositivelyregulate cellularproliferation(proto-oncogenes-KRAS,PIK3CA) cellcyclegenes-

cyclinD1,cyclinE,Cdc25A)Tumorsuppressors:

Genesencodingproteinsthatnegativelyregulatecellproliferation(tumorsuppressors-Rb,p16,ARF,PTEN,p53)Concept:MajorCategoriesofTumorGenomicAlterationsMajorCategoriesofTumorGenoGenetic/EpigeneticAlterationsLeadtoCancerOncogenes(Ras,PI3K)ActivationTumorSuppressors(p53,Rb,APC)InactivationLossofapoptosisProliferationCANCEREpigeneticeventsGenetic/EpigeneticAlterationsActivationofoncogenes(1)Pointmutations:

ChangeinasinglebasepairinDNAthatresultsinaminoacidsubstitution.HotspotmutationsinoncogeneVogelsteinBetal.Science.2013;339(6127):1546-1558E545KH1047R/LR132HActivationofoncogenes(1)PoinGain-of-functionmutationsinPIK3CASamuelYetalScience2004GkekaPetalPLoSComputBiol2014Gain-of-functionmutationsinGain-of-functionmutationsinNon-codingregionsTERTpromotermutationscreateconsensusETSsitesHuangF,etalScience2013HornS,etalScience2013BorahS,etalScience2015Gain-of-functionmutationsinActivationofoncogenes(2)CopynumberalterationsAbnormalDNAreplicationofaDNAsegmentincludingamplification(ERBB2)thatresultsingain-offunctionBeroukhimRetalNature2010Top20geneswithgainofcopynumberin26cancertypesActivationofoncogenes(2)CopyAmplificationofMycdrivesmanyoncogenicpathwaysActivegeneMycPromoterMycMycMycMycCancercellActivegenePromoterMycNormalcellAmplificationofMycdrivesmaChromosomaltranslocationsfusestwogenestogethertoproduceahybridgeneencodingachimericprotein,whoseactivity,unlikethatoftheparentproteins,oftenisconstitutive.Activationofoncogenes(3)MertensFetalNatureRevCancer2015ChromosomaltranslocationsActiSummary：ActivationofoncogenesSummary：Genetic/EpigeneticAlterationsLeadtoCancerOncogenes(Ras,PI3K)ActivationTumorSuppressors(p53,Rb,APC)InactivationLossofapoptosisProliferationCANCEREpigeneticeventsGenetic/EpigeneticAlterationsInactivationofTumorSuppressorGene(1)Pointmutations:

changeinasinglebasepairinDNAthatresultsinaminoacidsubstitution.Truncating/nonsensemutationsinTSGInactivationofTumorSuppress1.

Loss-of-functionmutationsinTP531.Loss-of-functionmutations2.

Loss-of-functionmutationsinChromatinmodifiers1.ARID1A(>30%)inOV2.PBRM1(>30%),SETD2(>10%)andBAP1(>10%)inccRCC3.CREBBP,MLL2/3andEP300inDLBCL4.KDM6AinBladdercancerRecurrentmutationsthatdisruptchromatinregulatorsoccurinmanycancersWatsonI,etalNatureReviewsGenetics20132.Loss-of-functionmutations3.

EpigenomicConsequencesofmutationsinchromatinmodifiersYaoetal,TrendsinCancer(2016)a)PointmutationsinDNMT3A,TET2,

IDH1/2,interferewithitsenzymaticactivityandinducefocalchangeson5mClevels.b)PointmutationinhistonevariantH3.3tailinhibitsthemethyltransferaseactivityofEZH2,causingaglobaldecreaseinH3K27me3c)InactivatingmutationsincomponentsoftheSWI/SNFchromatinremodelingcomplexdecreasenucleosomaloccupancyflankingthetranscriptionstartsited)InactivatingmutationsinhistonemethyltransferasesKMT2C/MLL3

andKMT2D/MLL2

decreaseH3K4me1/2atenhancers.e)Mutationsortranslocationinvolvingclassictumorsuppressorgeneandoncogenecanalsoaltertheepigeneticlandscape.3.EpigenomicConsequencesofInactivationofTumorSuppressorGene

(2)Copynumberalterations:

AbnormalDNAreplicationofaDNAsegmentincludingdeletion(RB1/PTEN/CDKN2A/B)thatresultsinloss-offunctionBeroukhimRetalNature2010Top20geneswithlossofcopynumberin26cancertypesInactivationofTumorSuppressInactivationofTumorSuppressorGene(3)DNAhypermethylationandhistonemodification.Adecadeofexploringthecancerepigenome—biologicalandtranslationalimplicationsBaylinSBandJonesPANatureReviewCancer2011InactivationofTumorSuppressBalmainA,etalNatureGenetics2003SummaryInactivationofTumorSuppressorGeneRB1PTENVHLBRCA1/2APCFBW7BalmainA,etalNatureGenetiGenetic/EpigeneticAlterationsLeadtoCancerOncogenes(Ras,PI3K)ActivationTumorSuppressors(p53,Rb,APC)InactivationLossofapoptosisProliferationCANCEREpigeneticeventsGenetic/EpigeneticAlterationsConcepts:Somemoleculesmayactasanoncogeneoratumorsuppressor,dependinguponthecell-typesandlocalizations.Concepts:Double-EdgedCharacteristicofNKX2-1/TTF-1CancerCell,Volume23,Issue6,718–723,2013NKX2-1/TTF-1hasshownbothoncogenicandinhibitoryactivitiesincancerdevelopmentandprogression.ReducedinvasionandmetastasisReducedKras-drivenlungtumorigenesisLineage-survivaloncogeneinlungadenocarcinomaOncogenicrearrangementinT-ALLGermlinemutationassociatedwiththyroidcancerEnhancedEgfr-drivenlungtumorigenesisOncogenicRolesSuppressiveRolesDouble-EdgedCharacteristicofLauE,KlugerH,VarsanoT,LeeK,SchefflerI,RimmDL,IdekerT,RonaiZA.PKCεpromotesoncogenicfunctionsofATF2inthenucleuswhileblockingitsapoptoticfunctionatmitochondria.Cell.2012Feb3;148(3):543-55.LauE,KlugerH,VarsanoT,LeProtein

Coding

RNA

VS

Non-coding

RNAProteinCodingRNAVSNon-codiTypesofoncogenesortumorsuppressors(1):Proteins:

Oncogenes-ras,HER2/neu,cyclinE,Cdc25A

Tumorsuppressors-Rb,p16,ARF,PTEN,p53.TypesofoncogenesortumorsuTypesofoncogenesortumorsuppressors(2):MicroRNAs(miRNAs,miR):Oncogenes-

themiRNA(miR)-17-92clustermiR372,miR373,miR155Tumorsuppressors-

let-7

(repressesRas)

miR-15a/-16-1(repressesBcl-2)

TypesofoncogenesortumorsuMicroRNAMicroRNAsareanaboundantclassofendogenoussmallRNAmolecules,20-25nucleotidesinlength.2.30%ofprotein-codinggenesmaybetargetedbymiRNAs.3.50%ofmicroRNAgenesarelocatedincancer-associatedgenomicregionsandinfragilesites.4.DirectcleavageofthetargetedmRNAorinhibitingtranslationthroughperfectornearlyperfectcomplementaritytotargetedmRNAatthe3’untranslatedregions(UTRs)oftargetsincells,inanimalsorplants.MicroRNAMicroRNAsareanabounMicroRNAscanfunctionastumorsuppressorsandoncogenesMicroRNAscanfunctionastumo癌基因与抑癌基因课件Typesofoncogenesortumorsuppressors(3):Longnon-codingRNAs(lncRNA):Non-proteincodingtranscriptslongerthan200nucleotides,morethan35000lncRNAsAcytoplasmicNF-κBinteractinglongnoncoding

RNA

blocksIκBphosphorylationandsuppressesbreastcancermetastasis.LiuB,SunL,LiuQ,GongC,YaoY,LvX,LinL,YaoH,SuF,LiD,ZengM,

SongE.CancerCell.2015Mar9;27(3):370-81.TheemergingroleoflncRNAsincancerTypesofoncogenesortumorsuMechanismsoflncRNAActionAdamSchmittandHowardChang,Cell2016A)Chromatin-boundlncRNAscanregulategeneexpressionbycontrollinglocalchromatinarchi-tecture(above)ordirectingtherecruitmentofregulatorymoleculestospecificloci(below).(B)lncRNAinteractionswithmultipleproteinscanpromotetheassemblyofproteincomplexes(above)orimpairprotein-proteininteractions(below).(C)mRNAinteractionswithlncRNAcanrecruitproteinmachineryinvolvedinmultipleaspectsofmRNAmetabolismtoaffectsplicing,mRNAstability,ortranslation(above)orsequestermiRNAawayfromtargetmRNA(below).MechanismsoflncRNAActionAdaAdamSchmittandHowardChang,Cell2016lncRNAsContributetotheHallmarksofCancerAdamSchmittandHowardChang,Protein

Coding

RNA

or

Non-coding

RNA

as

TSG

or

OncogeneProteinCodingRNAorNon-codiMultiplegeneticandepigeneticchangesincancerActivationofoncogenicsignalingpathwayleadstotumorigenesisCellsurvivalCelldeathGainoffunctionLossoffunctionPathwaysInter-connectedCancerisarobustsystemMultiplegeneticandepigenetiConcepts:Oncogenicsignalingpathway:pathwayswithactivatedoncogenesandinactivatedtumorsuppressorgenesthatconferaselectivegrowthadvantage

VogelsteinB,etalScience2013Cellfate:celldivisionordifferentiationCellSurvival:cellproliferationGenomemaintenance:DNAreplication(TP53,ATM)Concepts:VogelsteinB,etalSAberrantActivationofPI3K/AKTsignalingpathwayAberrantActivationofPI3K/AKClinicalImplicationsofCancerGenes3Equivalent

treatmentinthe

same

cancer

type:Differenttherapeutic

responsesDifferentclinical

outcomes

“Common

phenotype”

in

cancer

therapyClinicalImplicationsofCanceFromCancerGenomicstoDiagnosisPotentialbiomarkersinclinicaldiagnosisDCKoboldtetal.Nature000,1-10(2012)FromCancerGenomicstoDiagno2.PotentialtargetedtherapyforcancerRodon,J.et

al.

Nat.Rev.Clin.Oncol2013FromCancerGenomicstoTherapeutics2.PotentialtargetedtherapyApplication:anoncogeneoratumorsuppressor?2.Expressionincancercelllinesandcancertissues-clinicalrelevance.

3.Up-anddown-regulationincelllines:proliferation,apoptosis,transformation(growthonsoftagar),andtumorgenesis(tumorformationinnudemiceorNOD/SCID).4.Geneticallydisruptingthegene:homozygous,heterozygous,conditionalknock-out,ortransgenicanimals(spontaneousorinducibletumours).5.Determiningthemechanisms:well-knownoncogenesortumorsuppressors,suchasRAS,Myc,PTEN,p53.1.Literaturesearchforlatestupdateinthecandidategenes.

Application:2.ExpressioninOncologyLectureSeriesOncogenesandTumorSuppressorGenesOncologyLectureSeriesOncogenOverviewCancerandCancerGenomicsOncogenesandTumorSuppressorGenesClinicalImplicationsofCancerGenes123OverviewCancerandCancerGenoCancerandCancerGenomics1CancerandCancerGenomics190%Sporadiccancer10%Familialcancer,BRCA1/2CancerarisesfromgeneticandepigeneticalterationsinnormalcellulargenesMorethan200typesofcancerCancerisadiseaseofthegenomeVogelsteinB,etalScience2013BreakthroughExpansionInvasive90%SporadiccancerCancerarCarcinomas-cancersthatstartintheepithelialtissuessuchasskinortissuesthatlineorcoverinternalorgansSarcomas-cancerthatbeginsintheconnectiveorsupportivetissuessuchasbone,muscleorbloodvesselsLeukemia-cancerthatstartsinthebloodformingtissuesuchasbonemarrowLymphomaandMyeloma-cancersthatbegininthecellsoftheimmunesystemBrainandSpinalCordCancers-derivedfromcentralnervoussystemcancersMainCategoriesofCancerMainCategoriesofCancerCancerisComplexThehallmarksofcancer:thenextgeneration,Hannahan&Weinberg,Cell2011Metabolicdisease,Immunedisease,Environmentaldisease1.Sustainingproliferativesignaling2.Lossofgrowthsuppressors3.Apoptosisresistance4.Infiniteproliferativecapacity5.Angiogenicpotential6.InvasionandmetastasisSixMajorPathwaystocancer:CancergenomesCancerisComplexThehallmarksToobtaina

comprehensivedescriptionof

genomic,transcriptomicandepigenomicchanges

in

50differenttumortypesand/orsubtypes

whichareofclinicalandsocietalimportanceacrosstheglobe.(25000patients)Timeline:2010-Team:GlobalinstitutionsTogeneratecomprehensivedatasettodescribethemolecularchangesin33differenttumortypesfrom11000patientsTimeline:2005-2016Team:20collaboratinginstitutionsinUSandCanadaCancerGenomeProjectsToobtaina

comprehensivedescInternationalCancerGenomicStudiesDifferencein: EthnicityDietaryHabitsCarcinogen(eg.,betalnuts,AA)Pathogen(eg.,HPV,EBV,liverfluke)EnvironmentandPollutionInternationalCancerGenomicSHelicobacterpyloriGastricCancerOpisthorchisviverrini(LiverFluke)BileDuctCancer(Cholangiocarcinoma)AristolochiaPlants(egBirthwort)UrinaryTractCancerEpstein-BarrVirusNasopharyngealCancerPathogenandCarcinogensinAsianCancersHelicobacterGastricCancerOpisLBAlexandrovetal.Nature000,1-7(2013)doi:10.1038/nature12477TheprevalenceofsomaticmutationsacrosshumancancertypesMutationallandscapesfromwhole-genomesequencingof3281cancergenomesfrom12maincancertypesLBAlexandrovetal.Nature00SnapshotofCancerGenomicLandscape1AnOetalDatabase.doi:10.1093/database/2015.

2VogelsteinBetal.Science.2013;339(6127):1546-1558.SnapshotofCancerGenomicLan0-2drivermutationsinpediatrictumors3-6driversmutations(occasionally1-2)incommonadultNumberofdrivermutationspertumorVogelsteinB,etalScience20130-2drivermutationsinpediatCKandoth

etal.Nature502,333-339(2013)doi:10.1038/nature12634The127significantmutatedcancergenesidentifiedin12cancertypes.KRASPIK3CAPTENVHLAPCTP53OncogeneTumorsuppressorgenesEGFRRTK/RAS-PI3KsignalingCKandothetal.Nature502,3OncogenesandTumorSuppressorGenes2OncogenesandTumorSuppressorConcept:Oncogenes:

Genesencodingproteinsthatpositivelyregulate cellularproliferation(proto-oncogenes-KRAS,PIK3CA) cellcyclegenes-

cyclinD1,cyclinE,Cdc25A)Tumorsuppressors:

Genesencodingproteinsthatnegativelyregulatecellproliferation(tumorsuppressors-Rb,p16,ARF,PTEN,p53)Concept:MajorCategoriesofTumorGenomicAlterationsMajorCategoriesofTumorGenoGenetic/EpigeneticAlterationsLeadtoCancerOncogenes(Ras,PI3K)ActivationTumorSuppressors(p53,Rb,APC)InactivationLossofapoptosisProliferationCANCEREpigeneticeventsGenetic/EpigeneticAlterationsActivationofoncogenes(1)Pointmutations:

ChangeinasinglebasepairinDNAthatresultsinaminoacidsubstitution.HotspotmutationsinoncogeneVogelsteinBetal.Science.2013;339(6127):1546-1558E545KH1047R/LR132HActivationofoncogenes(1)PoinGain-of-functionmutationsinPIK3CASamuelYetalScience2004GkekaPetalPLoSComputBiol2014Gain-of-functionmutationsinGain-of-functionmutationsinNon-codingregionsTERTpromotermutationscreateconsensusETSsitesHuangF,etalScience2013HornS,etalScience2013BorahS,etalScience2015Gain-of-functionmutationsinActivationofoncogenes(2)CopynumberalterationsAbnormalDNAreplicationofaDNAsegmentincludingamplification(ERBB2)thatresultsingain-offunctionBeroukhimRetalNature2010Top20geneswithgainofcopynumberin26cancertypesActivationofoncogenes(2)CopyAmplificationofMycdrivesmanyoncogenicpathwaysActivegeneMycPromoterMycMycMycMycCancercellActivegenePromoterMycNormalcellAmplificationofMycdrivesmaChromosomaltranslocationsfusestwogenestogethertoproduceahybridgeneencodingachimericprotein,whoseactivity,unlikethatoftheparentproteins,oftenisconstitutive.Activationofoncogenes(3)MertensFetalNatureRevCancer2015ChromosomaltranslocationsActiSummary：ActivationofoncogenesSummary：Genetic/EpigeneticAlterationsLeadtoCancerOncogenes(Ras,PI3K)ActivationTumorSuppressors(p53,Rb,APC)InactivationLossofapoptosisProliferationCANCEREpigeneticeventsGenetic/EpigeneticAlterationsInactivationofTumorSuppressorGene(1)Pointmutations:

changeinasinglebasepairinDNAthatresultsinaminoacidsubstitution.Truncating/nonsensemutationsinTSGInactivationofTumorSuppress1.

Loss-of-functionmutationsinTP531.Loss-of-functionmutations2.

Loss-of-functionmutationsinChromatinmodifiers1.ARID1A(>30%)inOV2.PBRM1(>30%),SETD2(>10%)andBAP1(>10%)inccRCC3.CREBBP,MLL2/3andEP300inDLBCL4.KDM6AinBladdercancerRecurrentmutationsthatdisruptchromatinregulatorsoccurinmanycancersWatsonI,etalNatureReviewsGenetics20132.Loss-of-functionmutations3.

EpigenomicConsequencesofmutationsinchromatinmodifiersYaoetal,TrendsinCancer(2016)a)PointmutationsinDNMT3A,TET2,

IDH1/2,interferewithitsenzymaticactivityandinducefocalchangeson5mClevels.b)PointmutationinhistonevariantH3.3tailinhibitsthemethyltransferaseactivityofEZH2,causingaglobaldecreaseinH3K27me3c)InactivatingmutationsincomponentsoftheSWI/SNFchromatinremodelingcomplexdecreasenucleosomaloccupancyflankingthetranscriptionstartsited)InactivatingmutationsinhistonemethyltransferasesKMT2C/MLL3

andKMT2D/MLL2

decreaseH3K4me1/2atenhancers.e)Mutationsortranslocationinvolvingclassictumorsuppressorgeneandoncogenecanalsoaltertheepigeneticlandscape.3.EpigenomicConsequencesofInactivationofTumorSuppressorGene

(2)Copynumberalterations:

AbnormalDNAreplicationofaDNAsegmentincludingdeletion(RB1/PTEN/CDKN2A/B)thatresultsinloss-offunctionBeroukhimRetalNature2010Top20geneswithlossofcopynumberin26cancertypesInactivationofTumorSuppressInactivationofTumorSuppressorGene(3)DNAhypermethylationandhistonemodification.Adecadeofexploringthecancerepigenome—biologicalandtranslationalimplicationsBaylinSBandJonesPANatureReviewCancer2011InactivationofTumorSuppressBalmainA,etalNatureGenetics2003SummaryInactivationofTumorSuppressorGeneRB1PTENVHLBRCA1/2APCFBW7BalmainA,etalNatureGenetiGenetic/EpigeneticAlterationsLeadtoCancerOncogenes(Ras,PI3K)ActivationTumorSuppressors(p53,Rb,APC)InactivationLossofapoptosisProliferationCANCEREpigeneticeventsGenetic/EpigeneticAlterationsConcepts:Somemoleculesmayactasanoncogeneoratumorsuppressor,dependinguponthecell-typesandlocalizations.Concepts:Double-EdgedCharacteristicofNKX2-1/TTF-1CancerCell,Volume23,Issue6,718–723,2013NKX2-1/TTF-1hasshownbothoncogenicandinhibitoryactivitiesincancerdevelopmentandprogression.ReducedinvasionandmetastasisReducedKras-drivenlungtumorigenesisLineage-survivaloncogeneinlungadenocarcinomaOncogenicrearrangementinT-ALLGermlinemutationassociatedwiththyroidcancerEnhancedEgfr-drivenlungtumorigenesisOncogenicRolesSuppressiveRolesDouble-EdgedCharacteristicofLauE,KlugerH,VarsanoT,LeeK,SchefflerI,RimmDL,IdekerT,RonaiZA.PKCεpromotesoncogenicfunctionsofATF2inthenucleuswhileblockingitsapoptoticfunctionatmitochondria.Cell.2012Feb3;148(3):543-55.LauE,KlugerH,VarsanoT,LeProtein

Coding

RNA

VS

Non-coding

RNAProteinCodingRNAVSNon-codiTypesofoncogenesortumorsuppressors(1):Proteins:

Oncogenes-ras,HER2/neu,cyclinE,Cdc25A

Tumorsuppressors-Rb,p16,ARF,PTEN,p53.TypesofoncogenesortumorsuTypesofoncogenesortumorsuppressors(2):MicroRNAs(miRNAs,miR):Oncogenes-

themiRNA(miR)-17-92clustermiR372,miR373,miR155Tumorsuppressors-

let-7

(repressesRas)

miR-15a/-16-1(repressesBcl-2)

TypesofoncogenesortumorsuMicroRNAMicroRNAsareanaboundantclassofendogenoussmallRNAmolecules,20-25nucleotidesinlength.2.30%ofprotein-codinggenesmaybetargetedbymiRNAs.3.50%ofmicroRNAgenesarelocatedincancer-associatedgenomicregionsandinfragilesites.4.DirectcleavageofthetargetedmRNAorinhibitingtranslationthroughperfectornearlyperfectcomplementaritytotargetedmRNAatthe3’untranslatedregions(UTRs)oftargetsincells,inanimalsorplants.MicroRNAMicroRNAsareanabounMicroRNAscanfunctionastumorsuppressorsandoncogenesMicroRNAscanfunctionastumo癌基因与抑癌基因课件Typesofoncogenesortumorsuppressors(3):Longnon-codingRNAs(lncRNA):Non-proteincodingtranscriptslongerthan200nucleotides,morethan35000lncRNAsAcytoplasmicNF-κBinteractinglongnoncoding

RNA

blocksIκBphosphorylationandsuppressesbreastcancermetastasis.LiuB,SunL,LiuQ,GongC,YaoY,LvX,LinL,YaoH,SuF,LiD,ZengM,

SongE.CancerCell.2015Mar9;27(3):370-81.TheemergingroleoflncRNAsincancerTypesofoncogenesortumorsuMechanismsoflncRNAActionAdamSchmittandHowardChang,Cell2016A)Chromati