肿瘤细胞低氧反应的分子机制

©1994-2010ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.×Ø1,21.,8100012.,810001MolecularresponsestohypoxiaintumorcellsLIGuo2yuan1,GERi2li21.DepartmentofOncology,AffiliatedHospitalofQinghaiUniversity,Xining810001,P.R.China2.ResearchCenterofHighAltitudeMedicine,MedicalCollegeofQinghaiUniversity,Xining810001,P.R.China,,,,2006,13(17):1351-1354[ABSTRACT]Highlyaggressive,rapidlygrowingtumorsareexposedtohypoxiawhichoccursasaconsequenceofinadequatebloodsupply.Hypox2iaexertsavarietyofinfluencesontumorcellbiology.Theseareactivationofcertainsignaltransductionpathwaysandgeneregulatorymechanisms,inductionofselectionprocessesforgenemutations,tumorcellapoptosisandtumorangiogenesis.Mostofthesemechanismscontributetotumorprogression.Therefore,tissuehypoxiahasbeenregardedasacentralfactorfortumoraggressivenessandmetastasis.Inthisreview,wesummarizethecurrentknowledgeaboutthemolecularmechanismsinducedbytumorcellhypoxiawithaspecialemphasisonintracellularsignaltransduction,generegulation,angiogenesisandapoptosis.Interferingwiththesepathwaysmightopenperspectivesforfutureinnovativetreatmentofhighlyaggressivemetastasizingtumors.ChinJCancerPrevTreat,2006,13(17):1351-1354/;;;[KEYWORDS]neoplasms/pathology;anoxia;geneexpressionregulation;reviewliteratureR73-3A1673-5269(2006)17-1351-04,,,,,[1],,(mitogenactivatedprotein,MAP),,,,,Tel:[phone]E2mail:[e-mail],,,,,,Tel:[phone]E2mail:[e-mail][2],,,,/[3],,,,,p53,,1,Ras2Raf2MEK2ERK[4]AP21CREPEIK,1531200691317CHINJCANCERPREVTREAT,September2006,Vol.13No.17©1994-2010ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.(stress2activatedproteinkinases,SAPK)p38,JNK/SAPKp38,ATF22(mitogen2activatedproteinkinasephosphatase21,MKP21)mRNAMKP21,MKP21SAPK,MKP214hJNK/SAPKJNK/SAPK,,MAPK,,JNK/SAPK[2],,JNK/SAPK,p38[5],p38[6]JNK/SAPKc2Jun,Jun/Fos,c2Junc2Fos,,AP21JNK/SAPKc2Jun,Braf,BRAF,MAPRhoRasGTP[7],RasMAPKRhoGTPRhoC,DNARhoC,C,C,CRASGTPRAFRas2Raf2MEK2ERK2,(hy2poxiainduciblefactor,HIF)21,HIF2150[8],:1)(EPO);2);3)(VEGF);4)21(GLUT1);5)(HO21),HIF21DNA,HIF21HIF21(ARNT)HIF/ARNTCBP/P300[9]HIF21,,VHL[10],VHLVHL,HIF21HIFVEGF,HIFVHLHIF2HIF2122,CBP/P300C(CAD),HIF21FIH21CAD,CBP/P300,,,CBP/P300HIF21,FIH[11],HIF21ERK[12],HIF21VEGF,Ravip53,p53MdM2,MdM2HIF21,,p53HIF21VEGF,,HIF21,,HIF21[13]AP21,AP21,,,AP21AP21,JunFos,c2JunJNK/SAPK,AP21[14]RasRaf,NF2B,NF2B,2DNAp50p65,IKB,,IKB,p50p65,IKB/,IKB,NF2BAP21HIF21,c2JunmRNAc2JunNHIF21,,c2JunHIF21,,c2Jun2531,©1994-2010ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.(VEGFR21)KDR/Flk21(VEGR22)Flt4Tie21Tek/Tie22VEGFR22,VEGF,,RNA,170103,,,/,IL28,,VEGF,IL28HIF21,NF2BAP21,IL28,,ELRIL28IL28ELRMig21IP210,,IL28,IL28Cyr61,,,CCN[15],CCNCyr61V3V5,,Cyr61,AP21HIF21Cyr61Cyr61,,,RF21Cyr61[16]Cyr61[17]4,,,(mitochondrialpermeabilitytransi2tion,MPT),MPT,C,Apaf21,caspase9,Bcl22(Bcl22Bcl2XL)Bcl22BaxBax,C(ROS),,Bcl22Bcl22Nip3,caspase8Jurkat,caspase8,,caspase8,caspase8p53HIF21,HIF21p53HIF21[18],,PI23K2Akt,AKT/,,,AktBadBCL2XL[19]Akt,IKBaNF2B,Akt,PC12HER22/neu,PI23KLY294002[20]PTEN,,PIP2IP3,PI23K2AktPTEN,PTENPTEN,,PTENAkt,,VEGFPTEN,,3531200691317CHINJCANCERPREVTREAT,September2006,Vol.13No.17©1994-2010ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.[1]PeterBchler,HowardA.Reber,ManuelaBchler,etal.Hy2poxia2InducibleFactor1RegulatesVascularEndothelialGrowthFactorExpressioninHumanPancreaticCancer[J].Pancreas,2003,26(1):56-64.[2]KunzM,IbrahimS,KoczanD,etal.Activationofc2JunNH22terminalkinase/stress2activatedproteinkinase(JNK/SAPK)iscriticalforhypoxia2inducedapoptosisofhumanmalignantmela2noma[J].CellGrowthDiffer,2001,12(3):137-145.[3]AbbruscatoTJ,DavisTP.Proteinexpressionofbrainendo2thelialcellE2cadherinafterhypoxia/aglycemia:influenceofas2trocytecontact[J].BrainRes,1999,842(2):277-286.[4]ChangL,KarinM.MammalianMAPkinasesignallingcascade[J].Nature,2001,410(6824):37-40.[5]KunzM,BlossG,GillitzerR,etal.Hypoxia/reoxygenationin2ductionofmonocytechemoattractantprotein21inmelanomacells:involvementofnuclearfactor2kappaB,stimulatoryprotein21transcriptionfactorsandmitogen2activatedproteinkinasepath2ways.[J].BiochemJ,2002,366(Pt1):299-306.[6]TobiumeK,MatsuzawaA,TakahashiT,etal.ASK1isre2quiredforsustainedactivationsofJNK/p38MAPkinasesandapoptosis[J].EMBORep,2001,2(3):222-228.[7]ReutherGW,DerCJ.TheRasbranchofsmallGTPases:Rasfamilymembersdon’tfallfarfromthetree[J].CurrOpinCellBiol,2000,12(2):157-165.[8]SemenzaG.SignaltransductiontoHypoxia2InducibleFactor21[J].BiochenPharmacol,2002,64(5-6),993-998.[9]WengerRH.Cellularadaptationtohypoxia:O22sensingproteinhydroxylases,hypoxia2inducibletranscriptionfactors,andO22regu2latedgeneexpression[J].FASEBJ,2002,16(10):1151-1162.[10]KimW,KaelinWGJr.TheVonHippel2Lindautumorsup2pressorprotein:newinsightsintooxygensensingandcancer[J].CurrOpinGenetDev,2003,13(1):55