High expression of Cullin1 indicates poor prognosis for NSCLC patients

Pathology–ResearchandPractice210(2014)397–401

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Pathology–ResearchandPractice

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OriginalArticle

HighexpressionofCullin1indicatespoorprognosisforNSCLCpatients

MingmingXua,1,XiaomingYangb,1,JinliZhaoc,JianguoZhangd,ShuZhangd,HuaHuangd,YifeiLiud, ,JunhuaLiua,

a

DepartmentofCardiothoracicSurgery,Af liatedHospitalofNantongUniversity,Nantong226001,Jiangsu,ChinaDepartmentofNeuralBiology,NantongUniversity,Nantong226001,Jiangsu,Chinac

DepartmentofRadiology,Af liatedHospitalofNantongUniversity,Nantong226001,Jiangsu,Chinad

DepartmentofPathology,Af liatedHospitalofNantongUniversity,Nantong226001,Jiangsu,China

b

article

info

abstract

Articlehistory:

Received18October2013

Receivedinrevisedform5January2014Accepted30January2014

Keywords:

Non-small-celllungcancerCullin1

ProliferationPrognosis

Background:Cullin1isascaffoldproteinoftheubiquitinE3ligaseSkp1/Cullin1/Rbx1/F-boxproteincom-plexwhichubiquitinatesabroadrangeofproteinsparticipatinginbiochemicaleventslikecell-cycleprogression,signaltransduction,andtranscription.Cullin1isinvolvedintheprogressionofseveralcancers,suchasmelanoma,breastcancer,andgastriccancer.

Methods:ToinvestigatetheroleofCullin1inthedevelopmentofnon-small-celllungcancer(NSCLC),weexaminedtheexpressionofCullin1in8-pairedfreshNSCLCtissues.Wethenconstructedimmuno-histochemistry(IHC)on114paraf n-embeddedslicesandevaluatedthecorrelationbetweenCullin1expressionandclinicopathologicvariables,aswellaspatients’overallsurvival.

Results:WefoundthatCullin1washighlyexpressedinNSCLCtissuesandsigni cantlyassociatedwithNSCLC’shistologicaldifferentiation(P=0.002),clinicalstage(P=0.010)andKi-67(P=0.021).Further-more,weshowedastrongcorrelationbetweenhighCullin1expressionandworseoverallsurvivalratesinNSCLCpatients(P<0.001).CoxregressionanalysisrevealedthatCullin1expressionwasanindependentprognosticfactortopredict5-yearpatientoutcomeinNSCLCcancer(P=0.033).

Conclusion:ThesedatasuggestedthatCullin1mightpromotetheprogressionofNSCLCandbeabiotargetforNSCLC’stherapy.

©2014PublishedbyElsevierGmbH.

Introduction

Lungcancerremainstheleadingcauseofcancer-relateddeathsintheworld,mainlynon-small-celllungcancer(NSCLC)andsmall-celllungcancer(SCLC)[1].NSCLCconsistsoflungsquamouscellcarcinoma,lungadenocarcinomaandlarge-cellcarcinoma,whichisthehotspotoflungcancerresearch.TheincidenceofNSCLCisincreasing,owingtoenvironmentalpollutionandsmokingcigarette.The5-yearsurvivalrateismerely15%,althoughvari-ousadvancingtherapiescomeintouse[2].Lungcarcinogenesisisinvolvedinnumerousgeneticandepigeneticevents,suchasvari-ousoncogenes,tumorsuppressorgenes,cellcycleregulators,and

Correspondingauthorat:Af liatedHospitalofNantongUniversity,19QixiuRoad,Nantong,JiangsuProvince226001,China.Tel.:+8651385052118;fax:+8651385052118.

Correspondingauthorat:Af liatedHospitalofNantongUniversity,19QixiuRoad,Nantong,JiangsuProvince226001,China.Tel.:+8651385050901;fax:+8651385050901.

E-mailaddresses:blue ime@(Y.Liu), ime@(J.Liu).1

MingmingXuandXiaomingYangcontributedequallytothiswork.

DNArepairgenes.Thehighproliferativecapacityoflungtumor-ouscellsappearstobestronglyrelatedtoabnormalregulationthroughcriticalcheckpointsinvolvedincellcycleprogression[3].Soitisespeciallyimportanttoidentifynovelandselectivecell-cycle-relatedtargetsfortherapeuticinterventionofNSCLC.

Cancerdevelopmentistheprocessbywhichnormalcellsaretransformedintocarcinomacellsuponaberrantcellularstimuli.Thisprocessisregulatedbytranscription,translation,post-translationalmodi cationsanddegradationofkeyregulatoryproteinswhichhasacrucialroleinmaintainingandregulatingcel-lularhomeostasis[4,5].Speci cproteolysisofcell-cycleregulatorscanregulatethecell-cycleprogression[6],whiletwomajorE3lig-asecomplexes,Anaphase-promotingcomplex/cyclosome(APC/C)andSkp1/Cullin1/F-boxprotein(SCF)complex,ubiquitinatethetargetgenes[7].AsthemajorcategoryofE3ubiquitinligase,theSCFcomplexisinvolvedintheproteolysisofmaincomponentsofthecell-cycle-relatedproteins[8–10],regulatingtheexpressionofproteinsincellcycleprogression,suchasp53,p27,CDK,andcyclins[6,11–13].Ubiquitin-mediateddegradationofregulatoryproteinsplaysimportantrolesinG1-Stransition,signaltransductionandtranscriptionalregulation[14,15].AnaberrantE3ubiquitin

/10.1016/j.prp.2014.01.015

0344-0338/©2014PublishedbyElsevierGmbH.