NF-kB 启动因子

生命科学

letterstonature

AcknowledgementsWethankS.H.Ahn,D.Allis,M.Reyland,U.Siebenlist,theRockefellerUniversityGenotypingResourceCenterandtheMSKCCGenomicsCoreLaboratoryfor

providingcells,vectors,reagentsandtechnicalassistance.WealsothankE.Besmerforhelpwithmanuscriptpreparation,andA.PatkeandmembersoftheTarakhovskylaboratoryfordiscussions.ThisworkwassupportedbyTheIreneDiamondFund/ProfessorshipProgram(A.T.),theNIH(A.T.)andTheS.L.E.Foundation(I.M.).

CompetinginterestsstatementTheauthorsdeclarethattheyhavenocompeting nancialinterests.

CorrespondenceandrequestsformaterialsshouldbeaddressedtoA.T.(tarakho@mail.rockefeller.edu).

..............................................................

NF-kBfunctionsasatumourpromoterin

in ammation-associatedcancer

EliPikarsky1*,RinnatM.Porat1*,IlanStein1,2*,RinatAbramovitch3,SharonAmit2,Sha kaKasem1,ElenaGutkovich-Pyest2,SimchaUrieli-Shoval4,EithanGalun3&YinonBen-Neriah2

DepartmentofPathology,Hadassah-HebrewUniversityMedicalCenter,Jerusalem91120,Israel2

TheLautenbergCenterforImmunology,HebrewUniversity-HadassahMedicalSchool,Jerusalem91120,Israel3

GoldyneSavadInstituteofGeneTherapy,Jerusalem91120,Israel4

HematologyUnit,HadassahUniversityHospital,MountScopus,Jerusalem91120,Israel

*Theseauthorscontributedequallytothiswork

.............................................................................................................................................................................

1

Thecausesofsporadichumancancerareseldomrecognized,butitisestimatedthatcarcinogenexposureandchronicin am-mationaretwoimportantunderlyingconditionsfortumourdevelopment,thelatteraccountingforapproximately20%ofhumancancer1.Whereasthecausalrelationshipbetweencarcinogenexposureandcancerhasbeenintenselyinvestigated2,themolecularandcellularmechanismslinkingchronicin am-mationtotumorigenesisremainlargelyunresolved1.Wepro-posedthatactivationofthenuclearfactorkB(NF-kB),ahallmarkofin ammatoryresponses3thatisfrequentlydetectedintumours4,5,mayconstituteamissinglinkbetweenin ammationandcancer.Totestthishypothesis,westudiedtheMdr2-knock-outmousestrain,whichspontaneouslydevelopscholestatichepatitisfollowedbyhepatocellularcarcinoma6,aprototypeofin ammation-associatedcancer7.WemonitoredhepatitisandcancerprogressioninMdr2-knockoutmice,andhereweshowthatthein ammatoryprocesstriggershepatocyteNF-kBthroughupregulationoftumour-necrosisfactor-a(TNFa)inadjacentendothelialandin ammatorycells.SwitchingoffNF-kBinmicefrombirthtosevenmonthsofage,usingahepatocyte-speci cinducibleIkB-super-repressortransgene,hadnoeffectonthecourseofhepatitis,nordiditaffectearlyphasesofhepatocytetransformation.Bycontrast,suppressingNF-kBinhi-bitionthroughanti-TNFatreatmentorinductionofIkB-super-repressorinlaterstagesoftumourdevelopmentresultedinapoptosisoftransformedhepatocytesandfailuretoprogresstohepatocellularcarcinoma.OurstudiesthusindicatethatNF-kBisessentialforpromotingin ammation-associatedcancer,andisthereforeapotentialtargetforcancerpreventioninchronicin ammatorydiseases.

Hepatocellularcarcinoma(HCC),thethirdleadingcauseofcancermortalityworldwide,commonlydevelopsinthebackgroundofchronichepatitis8.Wecon rmedandextendedprevious

NATURE|VOL431|23SEPTEMBER2004|/nature

results6,9,accordingtowhichtumourdevelopmentintheMdr2-knockoutmouse,similarlytohumanHCC8,progressesthroughdistinctphases:in ammation,dysplasia,dysplasticnodules(ade-noma-like),carcinomaandmetastasis(SupplementaryFig.1a,b).HepatitisistheearliestsignofdiseaseintheMdr2-knockoutmice,andischaracterizedbyanextensiveperiductularandperiportalmixedin ammatoryin ltrate,richinCD3-positivecells(Sup-plementaryFig.1c).

NF-kBactivationisoftenobservedinhumanHCC,particularlyfollowinghepatitis8.ThepossibilitythatNF-kBactivationisinvolvedinMdr2-knockouthepatocarcinogenesiswasinvestigatedbyRelA(p65)immunostaining(Fig.1a).Nuclearstaining,indica-tiveofNF-kBactivation,wasevidentinknockoutliversofmiceatallages,butnotinnormal,age-matchedmice;thispromptedasearchforthesourceofNF-kBactivationintheknockoutmice.InsomeneoplasmssuchasHodgkin’sdiseaseandcertainlymphomas,NF-kBactivationisanintrinsic,tumourautonomousfeature,possiblyrelatedtomutationsinitssignallingpathway10.IfasimilarmechanismoccursinMdr2-knockoutHCC,onewouldobservenuclearNF-kBactivationinallneoplastichepatocytes.However,thiswasnotthecase;NF-kBactivationappearedscatteredattheparenchyma,predominantlyadjacenttoin amedportaltracts(Fig.1e,leftpanel),suggestinganin ammation-inducedphenom-enon.Toevaluatethispossibility,wefedknockoutandwild-typemicewiththenon-steroidalanti-in ammatorydrug(NSAID)ibuprofenfor10days.Thistreatmentresultedindecreasedin am-mation,evidentbyhistologicalanalysis(Fig.1b),decreasedserumalanineaminotransferase(ALT),amarkerforhepatocytedamage,(Fig.1c)andfewerneutrophils(Fig.1c,d).p65immunostainingshowedthatthedegreeofhepatocyteNF-kBactivationintheNSAID-treatedgroupwassigni cantlylowerthaninthecontrols(Fig.1e).Incontrast,ibuprofenhadnoeffectonhepatocyteNF-kBactivationfollowingintraperitonealTNFaadministration(datanotshown).Hence,itseemsthatNF-kBactivationintheknockouthepatocytesissecondarytoparenchymalin ltrationbyin amma-torycells.

搜索“diyifanwen.net”或“第一范文网”即可找到本站免费阅读全部范文。收藏本站方便下次阅读，第一范文网，提供最新人文社科NF-kB 启动因子全文阅读和word下载服务。