SMURF1 Amplification Promotes Invasiveness in Pancreatic Cancer 英文参考文献.docVIP

SMURF1AmplificationPromotesInvasivenessin PancreaticCancer KevinA.Kwei1.,A.HunterShain1.,RyanBair1,KelliMontgomery1,CollinsA.Karikari2,Mattvande Rijn1,ManuelHidalgo3,4,AnirbanMaitra2,MuraliD.Bashyam5,JonathanR.Pollack1* 1Department of Pathology, Stanford University, Stanford, California, United States of America, 2Department of Pathology, The Johns Hopkins University, Baltimore, Maryland,UnitedStatesofAmerica,3DepartmentofOncology,TheJohnsHopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica,4ClinicalResearchProgram, Centro Nacional de Investigaciones Oncolo′gicas, Madrid, Spain, 5Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad,India Abstract Pancreatic cancer is a deadly disease, and new therapeutic targets are urgently needed. We previously identified DNA amplificationat7q21-q22inpancreaticcancercelllines.Now,byhigh-resolutiongenomicprofilingofhumanpancreatic cancercelllinesandhumantumors(engraftedinimmunodeficientmicetoenrichthecancerepithelialfraction),wedefinea 325KbminimalampliconspanningSMURF1,anE3ubiquitinligaseandknownnegativeregulatoroftransforminggrowth factorb(TGFb)growthinhibitorysignaling.SMURF1amplificationwasconfirmedinprimaryhumanpancreaticcancersby fluorescence in situ hybridization (FISH), where 4 of 95 cases (4.2%) exhibited amplification. By RNA interference (RNAi), knockdownofSMURF1inahumanpancreaticcancerlinewithfocalamplification(AsPC-1)didnotaltercellgrowth,butled toreducedcellinvasionandanchorage-independentgrowth.Interestingly,thiseffectwasnotmediatedthroughaltered TGFbsignaling,assayedbytranscriptionalreporter.Finally,overexpressionofSMURF1(butnotacatalyticmutant)ledto lossofcontactinhibitioninNIH-3T3mouseembryofibroblastcells.Together,thesefindingsidentifySMURF1asanamplified oncogene driving multiple tumorigenic phenotypes in pancreatic cancer, and provide a new druggable target for molecularlydirectedtherapy. Citation:KweiKA,ShainAH,BairR,MontgomeryK,KarikariCA,etal.(2011)SMURF