HCV Tumor Promoting Effect Is Dependent on Host Genetic Background 英文参考文献.docVIP

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HCV Tumor Promoting Effect Is Dependent on Host Genetic Background 英文参考文献.doc

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HCV Tumor Promoting Effect Is Dependent on Host Genetic Background 英文参考文献

HCVTumorPromotingEffectIsDependentonHost GeneticBackground NaamaKlopstock1,MarkKatzenellenbogen2,OritPappo3,MiriamSklair-Levy4,DevorahOlam1 ,Lina Mizrahi1,TamaraPotikha1,EithanGalun1,DanielGoldenberg1* 1GoldyneSavadInstituteofGeneTherapy,Hadassah-HebrewUniversityMedicalCenter,Jerusalem,Israel,2BioinformaticsandMicroarrayUnit,TheMinaandEverard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel, 3Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 4BreastImagingCenter,ShebaMedicalCenter,TelHashomer,Israel Abstract Background:ThehepatitisCvirus(HCV)isoneofthemajorriskfactorsforthedevelopmentofhepatocellularcarcinoma (HCC). Nevertheless, transgenic mice which express the whole HCV polyprotein (HCV-Tg) do not develop HCC. Whereas chronicHCVinfectioncausesinflammationinpatients,inHCV-Tgmice,thehostimmunereactionagainstviralproteinsis lacking.WeaimedtotesttheroleofHCVproteinsinHCCdevelopmentonthebackgroundofchronicinflammationinvivo. Methodology/PrincipalFindings:WecrossedHCV-TgmicethatdonotdevelopHCCwiththeMdr2-knockout(Mdr2-KO) micewhichdevelopinflammation-associatedHCC,togenerateMdr2-KO/HCV-Tgmice.WestudiedtheeffectoftheHCV transgeneontumorincidence,hepatocytemitosisandapoptosis,andinvestigatedthepotentialcontributingfactorsforthe generatedphenotypebygeneexpressionandproteinanalyses.TheMdr2-KO/HCV-TgfemalesfromtheN2generationof thisbreeding(having75%oftheFVB/Ngenomeand25%oftheC57BL/6genome)producedsignificantlylargertumorsin comparisonwithMdr2-KOmice.Inparallel,theMdr2-KO/HCV-Tgfemaleshadanenhancedinflammatorygeneexpression signature.However,intheN7generation(having99.2%oftheFVB/Ngenomeand0.8%oftheC57BL/6genome)therewas nodifferenceintumordevelopmentbetweenMdr2-KO/HCV-TgandMdr2-KOanimalsofbothsexes.TheHCVtransgene wassimilarlyexpressedintheliversofMdr2-KO/HCV-Tgfemalesofbothgenerations,asrevealedbydetectionoftheHCV transcriptandthecoreprotein. Conclusion:ThesefindingssuggestthattheHCVtransgeneacceleratedinflamma