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1、Nuclearreceptorliverreceptorhomologue1(LRH-1)regulatespancreaticcancercellgrowthandproliferationCindyBenoda,MaiaV.Vinogradovaa,NataliaJouravela,GraceE.Kimb,RobertJ.Flettericka,1,andElenaP.SablinaaDepartmentofBiochemistryandBiophysics,UniversityofCalifornia60016thStreet,GHS412E,SanFranci
2、sco,CA94158-2517;andbDepartmentofPathology,UniversityofCalifornia505ParnassusAvenue,M561,SanFrancisco,CA94143-0102ContributedbyRobertJ.Fletterick,August18,2011(sentforreviewMay23,2011)Anessentialregulatorofgenetranscription,nuclearreceptorlivertordosagesensitivesexreversal,adrenalhypopl
3、asiacriticalreceptorhomologue1(LRH-1)controlscelldifferentiationintheregiononchromosomeXgene1(Dax-1)(3,16,17).NosyntheticdevelopingpancreasandmaintainscholesterolhomeostasisinantagonistsofLRH-1areavailabletodate.LRH-1islinkedtoadults.Recentgenome-wideassociationstudieslinkedmutationsmul
4、tipledevelopmentalpathwaysincludingWnt/β-catenin(8,intheLRH-1geneanditsup-streamregulatoryregionstodevelop-18),Hedgehogsignaling(19),andregulatorycascadescontrolledmentofpancreaticcancer.Inthiswork,weshowthatLRH-1tran-bythepancreas-specifictranscriptionfactorpancreaticandduo-scriptionis
5、activatedupto30-foldinhumanpancreaticcancercellsdenalhomeobox1(PDX-1)(20).Inpancreaticcancer,thesecomparedtonormalpancreaticductalepithelium.Thisactivationpathwaysarereactivatedandshowntobeessentialfordevelop-correlateswithmarkedlyincreasedLRH-1proteinexpressioninmentofpancreatictumors(
6、1,2,21,22).Recentgenome-widehumanpancreaticductaladenocarcinomasinvivo.Selectiveblock-associationstudieslinkmutationsintheLRH-1geneanditsingofLRH-1byreceptorspecificsiRNAsignificantlyinhibitspan-up-streamregulatoryregionstodevelopmentofPDAC(23).creaticcancercellproliferationinvitro.Thei
7、nhibitionistrackedInthisstudy,wedemonstratethattranscriptionofLRH-1inparttotheattenuationofthereceptor’stranscriptionaltargetsgeneismisregulated,anditsexpressionisactivatedinhumanSCIENCEScontrollingcellgrowth,proliferation,anddifferentiation.Pre-PDACscomparedtonormaladultpancre
