FXR Controls the Tumor Suppressor NDRG2 and FXR Agonists Reduce Liver Tumor Growth and Metastasis in an Orthotopic Mouse Xenograft Model 英文参考文献.docVIP

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FXR Controls the Tumor Suppressor NDRG2 and FXR Agonists Reduce Liver Tumor Growth and Metastasis in an Orthotopic Mouse Xenograft Model 英文参考文献.doc

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FXR Controls the Tumor Suppressor NDRG2 and FXR Agonists Reduce Liver Tumor Growth and Metastasis in an Orthotopic Mouse Xenograft Model 英文参考文献

FXRControlstheTumorSuppressorNDRG2andFXR AgonistsReduceLiverTumorGrowthandMetastasisin anOrthotopicMouseXenograftModel UlrichDeuschle1*,JuliaSchu¨ler2,AndreasSchulz1,ThomasSchlu¨ter1,OlafKinzel1,UlrichAbel3, ClausKremoser1 1DepartmentofResearch,PhenexPharmaceuticalsAG,Heidelberg,Germany,2DepartmentofInVivoTumorBiology,OncotestGmbH,Freiburg,Germany,3Department ofMedicinalChemistry,MerzPharmaceuticalsGmbH,Frankfurt,Germany Abstract ThefarnesoidXreceptor(FXR)isexpressedpredominantlyintissuesexposedtohighlevelsofbileacidsandcontrolsbile acid andlipid homeostasis. FXR2/2 mice develop hepatocellular carcinoma (HCC)andshow anincreased prevalence for intestinalmalignancies,suggestingaroleofFXRasatumorsuppressorinenterohepatictissues.TheN-mycdownstream- regulated gene 2 (NDRG2) has been recognized as a tumor suppressor gene, which is downregulated in human hepatocellularcarcinoma,colorectalcarcinomaandmanyothermalignancies. WeshowreducedNDRG2mRNAinliversof FXR2/2 mice compared to wild type mice and both, FXR and NDRG2 mRNAs, are reduced in human HCC compared to normal liver. Gene reporter assays and Chromatin Immunoprecipitation data support that FXR directly controls NDRG2 transcriptionviaIR1-typeelement(s)identifiedinthefirstintronsofthehuman,mouseandratNDRG2genes.NDRG2mRNA was induced by non-steroidal FXR agonists in livers of mice and the magnitude of induction of NDRG2 mRNA in three differenthumanhepatomacelllineswasincreasedwhenectopicallyexpressinghumanFXR.GrowthandmetastasisofSK- Hep-1 cells was strongly reduced by non-steroidal FXR agonists in an orthotopic liver xenograft tumor model. Ectopic expressionofFXRinSK-Hep1cellsreducedtumorgrowthandmetastasispotentialofcorrespondingcellsandincreasedthe anti-tumorefficacyofFXRagonists,whichmaybepartlymediatedviaincreasedNDRG2expression.FXRagonistsmayshow a potential in the prevention and/or treatment of human hepatocellular carcinoma, a devastating malignancy with increasingprevalenceandlimitedtherapeuticoptions. Cita