Global Demethylation of Rat Chondrosarcoma Cells after Treatment with 5-Aza-2′-Deoxycytidine Results in Increased Tumorigenicity 英文参考文献.docVIP

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Global Demethylation of Rat Chondrosarcoma Cells after Treatment with 5-Aza-2′-Deoxycytidine Results in Increased Tumorigenicity 英文参考文献.doc

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Global Demethylation of Rat Chondrosarcoma Cells after Treatment with 5-Aza-2′-Deoxycytidine Results in Increased Tumorigenicity 英文参考文献

GlobalDemethylationofRatChondrosarcomaCellsafter Treatmentwith5-Aza-29-DeoxycytidineResultsin IncreasedTumorigenicity ChristopherA.Hamm1,2,HehuangXie2,3,FabricioF.Costa2,ElioF.Vanin2,ElisabethA.Seftor2,SimoneT. Sredni2,JaredBischof2,DeliWang4,MariaF.Bonaldo2,3,MaryJ.C.Hendrix2,3,MarceloB.Soares2,3 * 1InterdisciplinaryGraduatePrograminGenetics,UniversityofIowa,IowaCity,Iowa,UnitedStatesofAmerica, 2CancerBiologyandEpigenomicsProgram,FalkBrain TumorCenter,Children’sMemorialResearchCenter,Chicago,Illinois,UnitedStatesofAmerica,3RobertH.LurieComprehensiveCancerCenter,NorthwesternUniversity’s FeinbergSchool ofMedicine,Chicago, Illinois, UnitedStates ofAmerica,4Biostatistics ResearchCore, Children’s Memorial ResearchCenter,NorthwesternUniversity’s FeinbergSchoolofMedicine,Chicago,Illinois,UnitedstatesofAmerica Abstract AbnormalpatternsofDNAmethylationareobservedinseveraltypesofhumancancer.WhilelocalizedDNAmethylationof CpGislandshasbeenassociatedwithgenesilencing,theeffectthatgenome-widelossofmethylationhasontumorigenesis isnotcompletelyknown.Toexamineitseffectontumorigenesis,weinducedDNAdemethylationinaratmodelofhuman chondrosarcomausing5-aza-2-deoxycytidine.Ratspecificpyrosequencingassayswereutilizedtoassessthemethylation levelsinbothLINEsandsatelliteDNAsequencesfollowing5-aza-2-deoxycytidinetreatment.LossofDNAmethylationwas accompaniedbyanincreaseininvasivenessoftheratchondrosarcoma cells,invitro,aswellasbyanincrease intumor growthinvivo.Subsequentmicroarrayanalysisprovidedinsightintothegeneexpressionchangesthatresultfrom5-aza-2- deoxycytidineinducedDNAdemethylation.Inparticular,twogenesthatmayfunctionintumorigenesis,sox-2andmidkine, wereexpressedatlowlevelsincontrolcellsbutupon5-aza-2-deoxycytidinetreatmentthesegenesbecameoverexpressed. Promoter region DNA analysis revealed that these genes were methylated in control cells but became demethylated following 5-aza-2-deoxycytidine treatment. Following withdrawal of 5-aza-2-deoxycytidine, the rat chond