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1、IJCInternationalJournalofCancerRNAi-mediatedMEK1knock-downpreventsERK1/2activationandabolisheshumanhepatocarcinomagrowthinvitroandinvivo1,2,31,2,31,2,31,2,31,3,4LucGailhouste,Fre´de´ricEzan,AnneBessard,ChristopheFre´min,JulieRageul,1,3,41,2,3,4SophieLangoue¨tandGeorgesBaffe
2、t1EA4427-SeRAIC,IFR140,Universite´deRennes1,F-35043Rennes,France2INSERMU522,IFR140,Universite´deRennes1,F-35043Rennes,France3Universite´Europe´ennedeBretagneUEB,F35043Rennes,France4INSERMU620,IFR140,Faculte´dePharmacie,F-35043Rennes,FranceThemitogen-activatedproteinkinasesM
3、EK/ERKpathwayregulatesfundamentalprocessesinmalignantcellsandrepresentsanattractivetargetinthedevelopmentofnewcancertreatmentsespeciallyforhumanhepatocarcinomahighlyresistanttochemotherapy.Althoughgeneextinctionexperimentshavesuggesteddistinctrolesfortheseproteins,theMEK/ER
4、Kcascaderemainswidelyconsideredasexhibitinganoverlapoffunctions.Toinvestigatethefunctionalityofeachkinaseintumorigenesis,wehavegeneratedstablyknock-downclonesforMEK1/2andERK1/2isoformsinthehumanhepatocellularcarcinomalineHuH7.OurresultshaveshownthatRNAistrategyallowsaspecif
5、icdisruptionofthetargetedkinasesandarguedforthecriticalfunctionofMEK1inlivertumorgrowth.TransientandstableextinctionexperimentsdemonstratedthatMEK1isoformactsasamajorelementinthesignaltransductionbyphosphorylatingERK1andERK2aftergrowthfactorsstimulation,whereasoncogenicleve
6、lofERK1/2phosphorylationappearstobeMEK1andMEK2dependentinbasalcondition.Inaddition,silencingofMEK1orERK2abolishedcellproliferationandDNAreplicationinvitroaswellastumorgrowthinvivoafterinjectioninrodent.Incontrast,targetingMEK2orERK1hadnoeffectonhepatocarcinomaprogression.Th
7、eseresultsstronglycorroboratetherelevanceoftargetingtheMEKcascadeasattestedbypharmacologicdrugsandsupportthepotentialapplicationofRNAiinfuturedevelopmentofmoreeffectivecancertherapies.OurstudyemphasizestheimportanceoftheCancerCellBiologyMEK/ERKpathwayinhumanhepatocarcinomac
8、ellgrowthandarguesforacrucialroleofMEK1andERK2inthisregulation.Thecanonicalsignali
