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TMPRSS2-ERGGeneFusionsinduceprostatetumorigenesisthroughmodulatingmicroRNAmiR-200cTMPRSS2-ERG基因融合通过调节miR-200c诱导前列腺肿瘤形成OncogeneImpactfactor:8.559
1AbbreviationsPCa:prostatecancer前列腺癌TMPRSS2:transmembraneprotease,serine2横跨膜的蛋白酶，丝氨酸2ETS:erythroblasttransformation-specific特异性有核红血球EMT:epithelial-to-mesenchymaltransition上皮间叶细胞转化Polycombgroupproteins:多梳家族蛋白（表观遗传调控因子polycomb复合蛋白被认为与多种肿瘤的发生发展有极大相关性，其中Rnf2在多种肿瘤中呈高表达。）
2BackgroundChromosomaltranslocationsthatjuxtaposetheandrogen-sensitivepromoteroftheTMPRSS2genetothecodingregionoftheoncogenicETSfamilytranscriptionfactorERGtermedTMPRSS2-ERGgenefusions,havebeenfoundin40–80%ofPCa.在40-80%的前列腺癌中出现TMPRSS2-ERG基因融合，这种基因融合将雄激素敏感的启动子TMPRSS2基因和编码区致癌ETS家族转录因子ERG融合的染色体易位称为TMPRSS2-ERG基因融合
3BackgroundmiRNAsarede-regulatedoftenthroughmechanismssuchaspromotermethylation（启动子甲基化）,genomicdeletion（基因缺失）,histonemodifications（组蛋白修饰）,andupstreamproteinalteration.SeveralmiRNAssuchasmiR-34,miR-145,andmiR-31havebeenshowntobedown-regulatedinPCapatients.Theyregulateimportantfactorssuchasc-Myc,stem-cellmarkers,andAR,therebycontrollingPCaprogression.
4BackgroundHartetal.showedthatmiR-145inhibitsERGexpressionbydirectlytargetingits3′UTR.LossofmiR-145mayprovideaTMPRSS2-ERGgenefusion-independentmeanstoERGup-regulationinPCa.Gordanpouretal.foundthatmiR-221isdown-regulatedinpatientswithtumorsbearingTMPRSS2-ERGgenefusions.However,nomechanisticstudieswerecarriedouttodeterminewhetherandhowERGregulatesmiR-221expression.
5IntroductionPurpose:IdentifymiRNAsthataredownstreamofERGandnominatemiR-200casarobustandimportantERG-regulatedmiRNA.ThelossofmiR-200cislinkedtopoordifferentiation(低分化)andstemcell-likecancercellsandisregulatedbyDNAmethylation,oncogeneactivation,orlossoftumorsuppressorgenessuchasp53.
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8ResultsmicroRNAexpressionprofilingnominatedmiR-200casadownstreamtargetofERG.ERGdirectlyregulatesmiR-200cexpression.ThemiR-200ctargetgenespredictERGstatusinprostatecancer.ERGinducesZEB1expressionthroughmodulatingmiR-200clevel.miR-200cmediatesERG-inducedcellmotility.
9DiscussionInthisstudy,weutilizedbioinformaticsapproachestointegrateERGChIP-SeqdatawithmiRNAprofilingdatatoidentifyarobustsetofmiRNAswhosecis-regulatoryelements(顺式调控元件)wereoccupiedbyERGandthatweredifferentiallyexpresseduponERGdysregulationinPCacells.AlthoughinthisstudywechosetofocusonmiR-200c,manyofthesemiRNAsmaysimilarlyplaysignificantrolesinERG-mediatedcellularprocessesandPCaprogression,whichcanbeimportantareasforfuturestudies.
10ThemiR-200cgenewasfoundtobedown-regulatedinvariousmetastatictypesofsolidtumorswhencomparedwithprimarytumors.ExtensiveresearchhasshownmiR-200ctoplaycriticalrolesininhibitingEMT,cellmotilityandtumormetastasisofvariouscancertypessuchasbreast,lungandcoloncancers.Discussion
11OurstudyisthefirsttodemonstratethatmiR-200cisadirecttargetofERGandisrepressedinERGfusion-positivePCa.Inaddition,weshowedthatmiR-200clossmediatesERG-inducedEMTandcellmotility.OurdatasuggestthattherapeuticdeliveryofmiR-200cmayprovidetargetedtreatmentofpatientswithERGfusion-positivePCa.Discussion
12WeshowedthatZEB1isatargetgeneofmiR-200cinPCaandmiR-200crevertedERG-inducedoncogenesisbyrepressingZEB1.However,miR-200cmightaffecttheexpressionofmanydownstreammoleculesinadditiontoZEB1.ConsideringtheessentialtumorsuppressiverolesofmiR-200cinPCaasdemonstratedinourstudy,itwarranteesfurtherinvestigationofmiR-200cdownstreamgenesorpathwaysinPCa.Discussion
13ConclusionThisstudycharacterizedthefirstERG-targetmiRNAgenemiR-200candsuggestedthatmiR-200creconstitutionmayprovidetargetedtherapiesforpatientswithTMPRSS2-ERGgenefusion-positivePCa.
14Thankyou
