An EMT–Driven Alternative Splicing Program Occurs in Human Breast Cancer and Modulates Cellular Phenotype 英文参考文献.docVIP
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An EMT–Driven Alternative Splicing Program Occurs in Human Breast Cancer and Modulates Cellular Phenotype 英文参考文献
AnEMT–DrivenAlternativeSplicingProgramOccursin
HumanBreastCancerandModulatesCellularPhenotype
IrinaM.Shapiro1.,AlbertW.Cheng2.,NicholasC.Flytzanis1,MicheleBalsamo1,JohnS.Condeelis3,
MajaH.Oktay4,ChristopherB.Burge5*,FrankB.Gertler1*
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 2Computational and
SystemsBiologyProgram,MassachusettsInstituteofTechnology,Cambridge,Massachusetts,UnitedStatesofAmerica,3DepartmentofAnatomy,AlbertEinsteinCollege
ofMedicine,Bronx,NewYork,UnitedStatesofAmerica,4DepartmentofPathology,MontefioreMedicalCenter,Bronx,NewYork,UnitedStatesofAmerica,5Department
ofBiologyandBiologicalEngineering,MassachusettsInstituteofTechnology,Cambridge,Massachusetts,UnitedStatesofAmerica
Abstract
Epithelial-mesenchymal transition(EMT),amechanismimportantforembryonicdevelopment, playsacriticalroleduring
malignant transformation. While much is known about transcriptional regulation of EMT, alternative splicing of several
geneshas also been correlated with EMT progression, but theextent of splicing changes andtheir contributions to the
morphological conversion accompanying EMT have not been investigated comprehensively. Using an established cell
culturemodelandRNA–Seqanalyses,wedeterminedanalternativesplicingsignatureforEMT.Genesencodingkeydrivers
of EMT–dependent changes in cell phenotype, such as actin cytoskeleton remodeling, regulation of cell–cell junction
formation,andregulationofcellmigration,wereenrichedamongEMT–associatedalternativelysplicingevents.Ouranalysis
suggested that most EMT–associated alternative splicing events are regulated by one or more members of the RBFOX,
MBNL, CELF, hnRNP, or ESRP classes of splicing factors. The EMT alternative splicing signature was confirmed in human
breastcancercelllines,whichcouldbeclassifiedintobasalandluminalsubtypesbasedexclusivelyontheirEMT–associated
splicing pattern. Expression of EMT–associated alternative mRNA t
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