UNCORRECTEDPROOF1PyruvatekinaseM2facilitatescoloncancercellmigrationviathe2modulationofSTAT3signalling3PengQ1Yanga,ZongweiLia,RongFua,HailiWua,ZhuoyuLia,b,⁎4aInstituteofBiotechnology,KeyLaboratoryofChemicalBiologyandMolecularEngineeringofNationalMinistryofEducation,ShanxiUniversity,Taiyuan030006,China5bCollegeofLifeScience,ZhejiangChineseMedicalUniversity,Hangzhou310053,ChinaabstractQ26articleinfo7Articlehistory:8Received14February20149Receivedinrevisedform15March201410Accepted15March201411Availableonlinexxxx12Keywords:13Colorectalcancer14PKM115PKM216Migration17Adhesion18Understandingthemechanismsofcolorectalcancer(CRC)metastaticprogressionisessentialtoreducingits19morbidityandmortality.Pyruvatekinase(PK)catalysesthefinalstepofglycolysisandhasbeenidentifiedasa20criticalregulatorofglucoseconsumption.However,themechanismsandrolesofPKM1andPKM2inthe21regulationofCRCcellmigrationandcelladhesionremainelusive.Here,wereportthatPKM2ratherthan22PKM1drivesCRCcellmigrationandcelladhesion,whereasPKMattenuationreversesthesephenomena.Further-23more,theoverexpressionofPKM2significantlyincreasestheexpressionofN-cadherin,MMP-2,MMP-9,STAT3,24Snail-2,pFAKandactiveβ1-integrin,whileE-cadherinexpressionissuppressed.Moreimportantly,theresults25indicatedthatPKM2overexpressionfacilitatesSTAT3nucleartranslocation,anditisrequiredforPKM2function26intheregulationofmigrationandadhesionassociatedsignalling.Inaddition,thedimericformofPKM2,which27lacksthepyruvatekinaseactivitiesbutpossessesproteinkinaseactivity,iscriticalforCRCcellmigrationand28celladhesion.Overall,thisstudysuggeststhatPKM2overexpressionpromotesCRCcellmigrationandcelladhe-29sionbyregulatingSTAT3-associatedsignallingandthatPKM2mayserveasatherapeutictargetforCRC30metastasis.31©2014PublishedbyElsevierInc.32333435361.Introduction37Unlikenormalcells,tumourcellsconsumelargeamountsofglucose38andproducemorelactatetogenerateenergyratherthanusingoxida-39tivephosphorylation,evenwhenoxygenisabundant[1].Becausethe40efficiencyofglycolysisin...
