Silencing of miR-370 in Human Cholangiocarcinoma by Allelic Loss and Interleukin-6 Induced Maternal to Paternal Epigenotype Switch 英文参考文献.docVIP

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Silencing of miR-370 in Human Cholangiocarcinoma by Allelic Loss and Interleukin-6 Induced Maternal to Paternal Epigenotype Switch 英文参考文献.doc

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Silencing of miR-370 in Human Cholangiocarcinoma by Allelic Loss and Interleukin-6 Induced Maternal to Paternal Epigenotype Switch 英文参考文献

SilencingofmiR-370inHumanCholangiocarcinomaby AllelicLossandInterleukin-6InducedMaternalto PaternalEpigenotypeSwitch FangmeiAn1,2,3,SumitakaYamanaka1,SarahAllen4,LewisR.Roberts5,GregoryJ.Gores5, TimothyM.Pawlik1,QingXie2,MasaharuIshida1,EstebanMezey1,AnneC.Ferguson-Smith4, YurikoMori1,FlorinM.Selaru1* 1Division of Gastroenterology and Hepatology, Johns Hopkins Hospital, Baltimore, Maryland, United States of America, 2Department of Infectious Diseases, Ruijin Hospital,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai,People’sRepublicofChina,3DepartmentofGastroenterology,WuxiPeople’sHospitalAffiliatedto NanjingMedicalUniversity,Wuxi,Jiangsu,China,4DepartmentofPhysiology,DevelopmentandNeuroscience,UniversityofCambridge,Cambridge,UnitedKingdom, 5DivisionsofGastroenterologyandHepatology,CollegeofMedicine,MayoClinic,Rochester,Minnesota,UnitedStatesofAmerica Abstract Cholangiocarcinoma(CCA)isahighlylethalmalignanttumorarisingfromthebiliarytractepithelium.Interleukin-6(IL-6)isa majormediatorofinflammationandcontributortocarcinogenesiswithinthebiliarytree.Previousstudiessuggestedthat enforced IL-6 contributes to cholangiocarcinogenesis through hypermethylation of several genes implicated in CCA. However,theprecisemechanismsofIL-6effectsinCCAremainunclear.WenowdemonstratethatmicroRNA(miR)-370is underexpressed in a large cohort of human CCA vs. normal liver tissues. In addition, we show that IL-6 induces a time- dependentsilencingofmiR-370.Inaddition,demethylationofCCAcellsresultsinupregulationofmiR-370.Furthermore,we demonstratethatmiR-370isimprinted,andthattheIntergenicDifferentiallyMethylatedRegion(IG-DMR)responsiblefor imprintingregulationofthisgenomiclocusishypermethylatedinresponsetoIL-6treatment.Inaddition,theIG-DMRis hypermethylatedinhumanCCAspecimenscomparedtonormalmatchedcontrols,inthesamelocationastheIL-6induced hypermethylation.Finally,miR-370wasfoundtoregulateWNT10Binluciferaseaswellaswesternblottingexperiments.Our data indicate that the paternal allele of miR