MicroRNA-210 Regulates Mitochondrial Free Radical Response to Hypoxia and Krebs Cycle in Cancer Cells by Targeting Iron Sulfur Cluster Protein ISCU 英文参考文献.docVIP

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MicroRNA-210 Regulates Mitochondrial Free Radical Response to Hypoxia and Krebs Cycle in Cancer Cells by Targeting Iron Sulfur Cluster Protein ISCU 英文参考文献.doc

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MicroRNA-210 Regulates Mitochondrial Free Radical Response to Hypoxia and Krebs Cycle in Cancer Cells by Targeting Iron Sulfur Cluster Protein ISCU 英文参考文献

MicroRNA-210RegulatesMitochondrialFreeRadical ResponsetoHypoxiaandKrebsCycleinCancerCellsby TargetingIronSulfurClusterProteinISCU ElenaFavaro1,2.,AnassuyaRamachandran2.,RobertMcCormick2,HarrietGee2,ChristineBlancher1, MeredithCrosby3,CeciliaDevlin4,ChristopherBlick2,FrancescaBuffa2,Ji-LiangLi2,BorivojVojnovic5, RicardoPiresdasNeves6,PeterGlazer3,FranciscoIborra6,MirceaIvan4*,JiannisRagoussis1,AdrianL. Harris2* 1GenomicsGroup,WellcomeTrustCentreforHumanGenetics,UniversityofOxford,Oxford,UnitedKingdom,2MolecularOncologyLaboratories,WeatherallInstituteof MolecularMedicine,UniversityofOxford,JohnRadcliffeHospital,Oxford,UnitedKingdom,3DepartmentofTherapeuticRadiology,YaleUniversitySchoolofMedicine, NewHaven,Connecticut,UnitedStatesofAmerica,4IndianaUniversity,Indianapolis,Indiana,UnitedStatesofAmerica,5GrayInstituteforRadiationOncologyBiology, University ofOxford, Oxford, United Kingdom, 6Molecular HaematologyLaboratories, Weatherall Institute ofMolecular Medicine, University ofOxford, JohnRadcliffe Hospital,Oxford,UnitedKingdom Abstract Background:Hypoxiaincancersresultsintheupregulationofhypoxiainduciblefactor1(HIF-1)andamicroRNA,hsa-miR- 210(miR-210)whichisassociatedwithapoorprognosis. Methods and Findings: In human cancer cell lines and tumours, we found that miR-210 targets the mitochondrial iron sulfurscaffoldproteinISCU,requiredforassemblyofiron-sulfurclusters,cofactorsforkeyenzymesinvolvedintheKrebs cycle, electron transport, and iron metabolism. Down regulation of ISCU was the major cause of induction of reactive oxygenspecies(ROS)inhypoxia.ISCUsuppressionreducedmitochondrialcomplex1activityandaconitaseactivity,caused ashifttoglycolysisinnormoxiaandenhancedcellsurvival.CancerswithlowISCUhadaworseprognosis. Conclusions: Induction of these major hallmarks of cancer show that a single microRNA, miR-210, mediates a new mechanism of adaptation to hypoxia, by regulating mitochondrial function via iron-sulfur cluster metabolism and free radicalgeneration. Citation:F