Alterations of the WNT7A Gene in Clear Cell Renal Cell Carcinomas 英文参考文献.docVIP

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Alterations of the WNT7A Gene in Clear Cell Renal Cell Carcinomas 英文参考文献.doc

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Alterations of the WNT7A Gene in Clear Cell Renal Cell Carcinomas 英文参考文献

AlterationsoftheWNT7AGeneinClearCellRenalCell Carcinomas AleksandrG.Kondratov1*,SergiyM.Kvasha1,LiubovA.Stoliar1,AlinaM.Romanenko2, YuryM.Zgonnyk2,VasilyV.Gordiyuk1,ElenaV.Kashuba4,5,AllaV.Rynditch3,EugeneR.Zabarovsky4,6,7, VladimirI.Kashuba1 1DepartmentofMolecularOncogenetics,InstituteofMolecularBiologyandGenetics,NationalAcademyofScience,Kyiv,Ukraine,2InstituteofUrology, Academyof Medical Sciences, Kyiv, Ukraine, 3Department of Functional Genomics, Institute of Molecular Biology and Genetics, National Academy of Science, Kyiv, Ukraine, 4DepartmentofMicrobiology,TumorandCellBiology(MTC),KarolinskaInstitute,Stockholm,Sweden,5R.E.KavetskyInstituteofExperimentalPathology,Oncologyand Radiobiology,NationalAcademyofScience,Kyiv,Ukraine,6LaboratoryofStructuralandFunctionalGenomics,EngelhardtInstituteofMolecularBiology,RAN,Moscow, Russia,7DepartmentofClinicalandExperimentalMedicine,FacultyofHealthSciences,LinkopingUniversity,Linkoping,Sweden Abstract WNT7A(wingless-typeMMTVintegrationsitefamily,member7A)isaknowntumorsuppressorgeneofnon-smallcelllung carcinomas(NSCLC)andisfrequentlyinactivatedduetoCpG-islandhypermethylationinhumancancers.Themembersof WNT family are involved in cell signaling and play crucial roles in cancer development. In the present work hypermethylation of the WNT7A gene was detected in 66% (29/44) of analyzed clear cell renal cell carcinomas (RCCs) usingmethyl-specificPCR(MSP).Moreover,bisulfitesequencingconfirmedintensivehypermethylationofthe59-CpGisland oftheWNT7Agene.Methylationanalysisrevealedpositivecorrelationsbetweentumorstage,Fuhrmannucleargradeand WNT7A hypermethylation. Additionally, restoration of WNT7A gene expression in the A498 cell line by 5-aza-29- deoxycytidine treatment confirmed a direct contribution of hypermethylation in silencing of the WNT7A gene. High frequencyoflossofheterozygosity(LOH)wasdemonstratedonchromosome3p25inregionssurroundingtheWNT7Agene. The frequent down-regulation of WNT7A gene expression was detected