MicroRNA93 Regulates Proliferation and Differentiation of Normal and Malignant Breast Stem Cells 英文参考文献.docVIP

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MicroRNA93 Regulates Proliferation and Differentiation of Normal and Malignant Breast Stem Cells 英文参考文献.doc

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MicroRNA93 Regulates Proliferation and Differentiation of Normal and Malignant Breast Stem Cells 英文参考文献

MicroRNA93RegulatesProliferationandDifferentiation ofNormalandMalignantBreastStemCells SulingLiu1*,ShivaniH.Patel1,ChristopheGinestier2,IngridIbarra3,RachelMartin-Trevino1, ShouminBai1,SeanP.McDermott1,LiShang1,JiaKe1,SingJ.Ou1,AmberHeath1,KevinJ.Zhang1, HasanKorkaya1,ShawnG.Clouthier1,EmmanuelleCharafe-Jauffret2,DanielBirnbaum2, GregoryJ.Hannon3,MaxS.Wicha1* 1Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America, 2Centre de Recherche en Cance′rologiedeMarseille,Laboratoired’OncologieMole′culaire, UMR891Inserm/InstitutPaoli-Calmettes,Universite′ delaMe′diterrane′e, Marseille,France,3Programin GeneticsandBioinformatics,ColdSpringHarborLaboratory,ColdSpringHarbor,NewYork,UnitedStatesofAmerica Abstract MicroRNAs (miRNAs) play important roles in normal cellular differentiation and oncogenesis. microRNA93 (mir-93), a memberofthemir106b-25cluster,locatedinintron13oftheMCM7gene,althoughfrequentlyoverexpressedinhuman malignanciesmayalsofunctionasatumorsuppressorgene.Usingaseriesofbreastcancercelllinesrepresentingdifferent stages of differentiation and mouse xenograft models, we demonstrate that mir-93 modulates the fate of breast cancer stemcells(BCSCs)byregulatingtheirproliferationanddifferentiationstates.In‘‘claudinlow’’SUM159cells,expressionofmir- 93inducesMesenchymal-EpithelialTransition(MET)associatedwithdownregulationofTGFbsignalinganddownregulates multiplestemcellregulatorygenes,includingJAK1,STAT3,AKT3,SOX4,EZH1,andHMGA2,resultingincancerstemcell (CSC) depletion. Enforced expression of mir-93 completely blocks tumor development in mammary fat pads and developmentofmetastasesfollowingintracardiacinjectioninmousexenografts.Theeffectofmir-93ontheCSCpopulation isdependentonthecellulardifferentiationstate,withmir-93expressionincreasingtheCSCpopulationinMCF7cellsthat display a more differentiated ‘‘luminal’’ phenotype. mir-93 also regulates the proliferation and differentiation of normal