Ataxia-Telangiectasia Group D Complementing Gene (ATDC) Promotes Lung Cancer Cell Proliferation by Activating NF-κB Pathway.docVIP

Ataxia-TelangiectasiaGroupDComplementingGene (ATDC)PromotesLungCancerCellProliferationby ActivatingNF-k BPathway Zhong-PingTang1,Qian-ZeDong1,Quan-ZheCui1,PauliePapavassiliou2,En-DiWang2,En-HuaWang1* 1Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang City, China, 2Department of Pathology,DukeUniversityMedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica Abstract PreviousstudiessuggestedAtaxia-telangiectasiagroupDcomplementinggene(ATDC)asanoncogeneinmanytypesof cancer.However,itsexpressionandbiologicalfunctionsinnon-smallcelllungcancer(NSCLC)remainunclear.Herein,we investigateditsexpressionpatternin109casesofhumanNSCLCsamplesbyimmunohistochemistryandfoundthatATDC wasoverexpressedin62of109NSCLCsamples(56.88%).ATDCoverexpressioncorrelatedwithhistologicaltype(p,0.0001), tumor status (p=0.0227) and histological differentiation (p=0.0002). Next, we overexpressed ATDC in normal human bronchialepithelialcelllineHBEanddepleteditsexpressioninNSCLCcelllinesA549andH1299.MTTandcolonyformation assayshowedthatATDCoverexpressionpromotedcellproliferationwhileitsdepletioninhibitedcellgrowth.Furthermore, cell cycle analysis showed that ATDC overexpression decreased the percentage of cells in G1 phase and increased the percentageofcellsinSphase,whileATDCsiRNAtreatmentincreasedtheG1phasepercentageanddecreasedtheSphase percentage.FurtherstudyrevealedthatATDCoverexpressioncouldup-regulatecyclinD1andc-MycexpressioninHBEcells while its depletion down-regulated cyclin D1 and c-Myc expression in A549 and H1299 cells. In addition, ATDC overexpressionwasalsoassociatedwithanincreasedproliferationindex,cyclinD1andc-MycexpressioninhumanNSCLC samples.FurtherexperimentsdemonstratedthatATDCup-regulatedcyclinD1andc-Mycexpressionindependentofwnt/b- cateninorp53signalingpathway.Interestingly,ATDCoverexpressionincreasedNF-kBreporterluciferaseactivityandp-IkB protein level. Correspondingly, NF-kB inhibitor blocked the e