High expression of Cullin1 indicates poor prognosis for NSCLC patients(6)

400

M.Xuetal./Pathology–ResearchandPractice210(2014)397–401

Fig.2.RepresentativemicrophotographsforCullin1byIHCinNSCLC.

Table2

ContributionofvariouspotentialprognosticfactorstosurvivalbyCoxregressionanalysisin114NSCLCspecimens.

Hazardratio

AgeGenderTumorsize

SmokingstatusHistologicaltypeClinicalstage

HistologicaldifferentiationLymphnodestatusCullin1expressionKi-67expression

95.0%Con denceinterval

P0.3340.1420.002*0.1900.2050.023*<0.001*0.0550.033*<0.001*

1.2400.6912.0751.4160.7651.3642.7580.6710.5772.464

0.802–1.9200.421–1.1321.305–3.3010.841–2.3850.505–1.1581.044–1.7842.020–3.7650.447–1.0080.347–0.9581.495–4.059

Note:StatisticalanalyseswereperformedbytheCoxregressionanalysis.*

P<0.05wasconsideredsigni cant.

Fig.3.CorrelationbetweenCullin1expressionandpatients’survival.

Asageneralrule,normalcellproliferationdependsonanorderlyandef cientlycellcycleprocesswhichensurestheduplicationandtransductionofgeneticinformationduringcellgeneration[23].Dysregulationofcellproliferationalwaysledtoanabnor-malcellcycle,whichwasthefundamentalofcarcinogenesis.Theubiquitin–proteasomesystemplayedacrucialroleinmain-tainingthebalancebetweennormalgrowthanduncontrolledproliferation,regulatingcellularhomeostasisandcontrolingtheabundanceofavarietyofcellularproteins,including -catenin,P27,andcyclins[24–27].TheSCFcomplex,acoreelementoftheubiquitin–proteasomesystem,playedwellestablishedrolesincellgrowth.Cullins,asscaffoldproteins,couldendowmulti-mericcomplexofE3ligaseswithsubstratespeci city[28].Cullin1,asascaffoldproteinoftheSCFcomplex,hadakeyroleintheubiquitin-dependentdegradationpathwayregulatingtheexpres-sionofcyclins(cyclinD1andcyclinG1)andCDKinhibitors(p27andp21)[29,30].Cullin1-mediatedsubstratedegradationdictatedawiderangeofcellularprocessessuchasproliferation,differ-entiation,andapoptosis[23].PreviousstudiesfoundthatCullin1regulatedcyclinEdegradation[28].LossofCullin1resultedinearlyembryoniclethalityanddysregulationofcyclinE[31].

ManyrecentstudieshavedemonstratedthatCullin1overex-pressionisassociatedwithvariousmalignanttumors,likegastriccancerandmalignantmelanoma[24,32].Cullin1mightintegratewithSkp2toregulateG1-StransitioningastriccancerviaSkp2-dependentp27degradation[24].Inparticular,Cullin1,themostcharacterizedmemberoftheCullinfamily,predictedpoorprog-nosisofpatientswithgastriccarcinomawhenoverexpressed[24].HighCullin1expressionwassigni cantlycorrelatedwithworseoverallsurvivalinbreastcancerpatients[33].Inaddition,Cullin1wasreportedtopromotetrophoblastinvasionandmigration,basedonseverallinesofevidence[29].Sinceuncontrolledcelldivisionwasafeatureofoncogenesis,itwastemptingforustoconjec-turetheroleofCullin1inNSCLC.Firstly,wefoundthatCullin1washighlyexpressedinNSCLCfreshtissuescomparedwithadja-centnormaltissues(Fig.1).Thiswascon rmedbyIHCon114