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1、Oncogene(2015),1–12©2015MacmillanPublishersLimitedAllrightsreserved0950-9232/15www.nature.com/oncORIGINALARTICLEInductionofmiRNA-181abygenotoxictreatmentspromoteschemotherapeuticresistanceandmetastasisinbreastcancer1,2,63,62,4,54,51,231,21,24,51,24,51,2JNiu,AXue,YChi,JXue,WWang,ZZhao,M
2、Fan,CHYang,Z-MShao,LMPfeffer,JWuandZ-HWuAcquiredtherapeuticresistanceisthemajordrawbacktoeffectivesystemictherapiesforcancers.Aggressivetriple-negativebreastcancers(TNBC)developresistancetochemotherapiesrapidly,whereastheunderlyingmechanismsarenotcompletelyunderstood.Hereweshowthatgeno
3、toxictreatmentssignificantlyincreasedtheexpressionofmiR-181ainTNBCcells,whichenhancedTNBCcellsurvivalandmetastasisuponDoxorubicintreatment.Consistently,highmiR-181alevelassociatedwithpoordiseasefreesurvivalandoverallsurvivalaftertreatmentsinbreastcancerpatients.TheupregulationofmiR-181a
4、wasorchestratedbytranscriptionfactorSTAT3whoseactivationdependedonNF-κB-mediatedIL-6inductioninTNBCcellsupongenotoxictreatment.Intriguingly,activatedSTAT3notonlydirectlyboundtoMIR181A1promotertodrivetranscriptionbutalsofacilitatedtherecruitmentofMSK1tothesameregionwhereMSK1promotedaloc
5、alactivechromatinstatebyphosphorylatinghistoneH3.WefurtheridentifiedBAXasadirectfunctionaltargetofmiR-181a,whosesuppressiondecreasedapoptosisandincreasedinvasionofTNBCcellsuponDoxtreatment.TheseresultswerefurtherconfirmedbyevidencethatsuppressionofmiR-181asignificantlyenhancedtherapeuticr
6、esponseandreducedlungmetastasisinaTNBCorthotopicmodel.Collectively,ourdatasuggestedthatmiR-181ainductionhadacriticalroleinpromotingtherapeuticresistanceandaggressivebehaviorofTNBCcellsupongenotoxictreatment.AntagonizingmiR-181amayserveasapromisingstrategytosensitizeTNBCcellstochemother
7、apyandmitigatemetastasis.Oncogeneadvanceonlinepublication,1June2015;doi:10.1038/onc.2015.189INTRODUCTIONgenesaretranscribedintoprimary-miRNAsbyRNApolymeraseII,Astriple-negativebreastcancers(TNBC)lackmoleculartargets,whichcanbesequentiallyprocessedintomaturemiRNAs.Thechemotherapyisthe
