An RNA Interference Phenotypic Screen Identifies a Role for FGF Signals in Colon Cancer Progression 英文参考文献.docVIP

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An RNA Interference Phenotypic Screen Identifies a Role for FGF Signals in Colon Cancer Progression 英文参考文献.doc

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An RNA Interference Phenotypic Screen Identifies a Role for FGF Signals in Colon Cancer Progression 英文参考文献

AnRNAInterferencePhenotypicScreenIdentifiesaRole forFGFSignalsinColonCancerProgression MarcLeushacke1,2,RalfSpo¨rle1,ChristofBernemann1,AntjeBrouwer-Lehmitz1,JohannesFritzmann3,4, MirkoTheis5,6,FrankBuchholz5,6,BernhardG.Herrmann1,7,MarkusMorkel1* 1Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany, 2Department of Biology, Chemistry and Pharmacy, Free UniversityBerlin,Berlin,Germany,3MaxDelbru¨ckCenterforMolecularMedicine,Berlin,Germany,4DepartmentofSurgery,HeidelbergUniversityHospital,Heidelberg, Germany,5MaxPlanckInstitute ofMolecularCellBiologyandGenetics,Dresden,Germany, 6UniversityHospitalCarlGustavCarusandMedicalFaculty, Universityof TechnologyDresden,Dresden,Germany,7InstituteforMedicalGenetics,Charite′ CampusBenjaminFranklin,Berlin,Germany Abstract In tumor cells, stepwise oncogenic deregulation of signaling cascades induces alterations of cellular morphology and promotestheacquisitionofmalignanttraits.Here,weidentifiedasetof21genes,includingFGF9,asdeterminantsoftumor cellmorphologybyanRNAinterferencephenotypicscreeninSW480coloncancercells.Usingapanelofsmallmolecular inhibitors, we subsequently established phenotypic effects, downstream signaling cascades, and associated gene expressionsignaturesofFGFreceptorsignals.WefoundthatinhibitionofFGFsignalsinducesepithelialcelladhesionand lossofmotilityincoloncancercells.Theseeffectsaremediatedviathemitogen-activatedproteinkinase(MAPK)andRho GTPase cascades. In agreement with these findings, inhibition of the MEK1/2 or JNK cascades, but not of the PI3K-AKT signalingaxisalsoinducedepithelialcellmorphology.Finally,wefoundthatexpressionofFGF9wasstronginasubsetof advanced colon cancers, and overexpression negatively correlated with patients’ survival. Our functional and expression analysessuggestthatFGFreceptorsignalscancontributetocoloncancerprogression. Citation:LeushackeM,Spo¨rleR,BernemannC,Brouwer-LehmitzA,FritzmannJ,etal.(2011)AnRNAInterferencePhenotypi