Knockdown of Oct4 and Nanog expression inhibits the stemness of pancreatic cancer cells

胰腺癌肿瘤干细胞研究

KnockdownofOct4andNanogexpressioninhibitsthestemnessofpancreaticcancer

cells

YuhuaLua,b,c,1,HuiZhua,1,HaiyanShanb,JunjieLub,XuChangb,XiaohongLia,JingjingLua,

XiangjunFanb,ShajunZhub,YaoWangb,QingsongGuob,LeiWangb,YanHuangb,MingyanZhub, ,ZhiweiWangb,

a

SurgicalComprehensiveLaboratory,Af liatedHospitalofNantongUniversity,Nantong,JiangsuProvince226001,PRChinaDepartmentofGeneralSurgery,Af liatedHospitalofNantongUniversity,Nantong,JiangsuProvince226001,PRChinac

VisitorScholarofWakeForestInstituteforRegenerativeMedicine,WakeForestUniversitySchoolofMedicine,Winston-Salem,NC27101,USA

b

articleinfoabstract

Pancreaticcancerisnotoriousforitsdif cultdiagnosisatearlystageandpoorrecurrence-freeprognosis.ThisstudyaimedtoinvestigatethepossibleinvolvementofOct4andNanoginpancreaticcancer.ThehighexpressionsofOct4andNanoginhumanpancreaticcancertissueswerefoundtoindicateaworseprognosticvalueofpatients.Thepancreaticcancerstemcells(PCSCs)thatisolatedfromPANC-1celllineby owcytometryexhibitedhighexpressionsofOct4andNanog.ToinvestigatewhetherOct4andNanogplaycrucialroleinmaintainingthestemnessofPCSCs,doubleknockdownofOct4andNanogdemon-stratedthatOct4andNanogsigni cantlyreducedproliferation,migration,invasion,chemoresistance,andtumorigenesisofPCSCsinvitroandinvivo.Thealteredexpressionofthegenesrelatedtopancreaticcarcinogenesis,metastasis,drugresistanceandepithelial–mesenchymaltransdifferentiation(EMT)mightaffectthebiologicalcharacteristicsofPCSCs.OurresultssuggestthatOct4andNanogmayserveasapotentialmarkerofprognosisandanoveltargetoftherapyforpancreaticcancer.

Ó2013ElsevierIrelandLtd.Allrightsreserved.

Articlehistory:

Received6May2013

Receivedinrevisedform4July2013Accepted10July2013

Keywords:

PancreaticcancerCancerstemcellsOct4Nanog

1.Introduction

Pancreaticcancerisafairlycommonmalignantneoplasmwiththepoorprognosisandhighfrequencyofrecurrenceormetastasisintheworld[1–4].Duetothelackofappropriatetoolsandspeci csymptomsforearlydiagnosis,pancreaticcancerhaspoorsurvivalrates[5,6].

Anumberofstudieshavedemonstratedthepresenceofcancerstemcells(CSCs)insolidtumors.Untilnow,CSCshavebeeniden-ti edinmanymalignanttumorsincludingskin,pancreas,brainandovarian[7–10].TheCSCsareinvolvedintumorinitiation,development,metastasisandreoccur[11,12].Lietal. rstlyre-portedtheseparationandidenti cationofPCSCsbytheCD24+-CD44+ESA+phenotype[13].ThePCSCssharetwodistinctivepropertieswithembryonicstemcells(ESCs):anunlimitedcapacityforself-renewalandpluripotency,whiletheyalsohaveahighcapacityfordrugresistanceandmetastaticactivity[14–16].FortheisolationofPCSCsfrompancreaticadenocarcinomacellline,thesubpopulationcells(CD24+CD44+ESA+)havepropertiesofCSCs[5,17].

Correspondingauthors.Tel.:+8651381161108;fax:+8651385519820.

1

E-mailaddress:wzw3639@http://doc.xuehai.net(Z.Wang).Theseauthorscontributedtothisworkequally.

BothOct4andNanogarecrucialtranscriptionalregulatorsre-quiredtomaintaintheself-renewalandpluripotencyofESCs.EmergingevidencehasdemonstratedthatOct4geneplaysanimportantroleduringmultiplebiologicalprocessessuchasprolif-eration,differentiation,stressresponseandapoptosisinstemcells[18].AndNanogisdown-regulatedduringEScelldifferentiation.LossofNanogexpressiondirectlyimpactsonthedevelopmentofESCs.ThegeneregulatorynetworkinvolvedwithOct4andNanogdoesnotonlyinducetheirownencodinggenesthatencodethekeycomponentpartsinsignaltransduction,butalsoinhibitssomegenesthatplayacrucialroleindevelopment.Furthermore,itreg-ulatedpluripotencyandself-renewalofESCsorearlydevelopmentoforganisms.

Strongevidenceshavesuggestedthatover-expressionsofOct4andNanogarecloselyrelatedtotumorigenesis,tumortransforma-tion,tumormetastasisanddistantrecurrenceafterchemoradio-therapy[19,20].Bothofthemhavealsobeenfoundtobecrucialregulatorsofself-renewalinCSCsandmayactascrucialmolecularcomponentsthatdetermineCSCcellfateduringcancerdevelop-ment[21–23].Forexample,Nanogwasfoundtobeupregulated,whichenhancedtheexpressionoftypicalCSCmarkers,suchasCD133,ABCG2,ALDH1A1andCD44inprostatecancer[24].AndOct4wassimilarlyupregulatedinCSCsofgynecologicalmalignancies[25].However,theroleofOct4andNanogsignalinginPCSCsisstillelusive.

0304-3835/$-seefrontmatterÓ2013ElsevierIrelandLtd.Allrightsreserved.http://doc.xuehai.net/10.1016/j.canlet.2013.07.009

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