Oncotarget1www.impactjournals.com/oncotargetwww.impactjournals.com/oncotarget/Oncotarget,AdvancePublications2016FOXO1inhibitstheinvasionandmetastasisofhepatocellularcarcinomabyreversingZEB2-inducedepithelial-mesenchymaltransitionTianxiuDong1,YuZhang1,YaodongChen1,PengfeiLiu2,TingtingAn1,JiuweiZhang1,HaichaoYang1,WenjingZhu1,XiuhuaYang11DepartmentofAbdominalUltrasound,TheFirstAffiliatedHospitalofHarbinMedicalUniversity,Harbin150001,China2DepartmentofMagneticResonanceImaging,TheFirstAffiliatedHospitalofHarbinMedicalUniversity,Harbin150001,ChinaCorrespondenceto:XiuhuaYang,email:xhyang2016@163.comKeywords:FOXO1,hepatocellularcarcinoma,epithelial-mesenchymaltransition,ZEB2,TGF-βReceived:March24,2016Accepted:November02,2016Published:December03,2016ABSTRACTTheepithelial-to-mesenchymaltransition(EMT)programiscriticalforepithelialcellcancerprogressionandfibroticdiseases.FOXO1influencesabroadrangeofphysiologicalandpathologicalprocesses.However,themechanismbywhichFOXO1inhibitsEMTisnotfullyunderstood.Inthisstudy,wedemonstratedthatFOXO1overexpressioninhibitedcellmotilityandinvasivenessinvitroandinhibitedlungmetastasisinvivo.Inaddition,wefoundthatFOXO1couldreversetheEMTprogram.FOXO1silencingbysiRNAinhepatocellularcarcinoma(HCC)celllinesenhancedtheexpressionofmesenchymalmarkersanddecreasedtheexpressionoftheepithelialmarkers.Consistentwiththesefindings,FOXO1overexpressionexertedoppositeeffects.Furthermore,wefoundthatFOXO1levelswereinverselycorrelatedwiththelevelsofEMTinducers,includingSnail,Slug,ZEB1,ZEB2andTwist1inHCCcells.Co-immunoprecipitationandimmunohistochemistryassaysrevealedthataninteractionbetweenFOXO1andZEB2.Adual-luciferasereporterassayandaChIPassayfurtherdemonstratedthatFOXO1bindstotheZEB2promoter.Together,thesefindingssuggestthatFOXO1overexpressionorZEB2inhibitionmightbepotentialtherapeuticstrategiesfortreatingHCC.INTRODUCTIONHepatocellularcarcinoma(HCC)isoneofthemostcommonsolidmalignanciesworldwideandisthesecondleadingcauseofcancer-relatedmortalityinAsia[1].Thepro...
