Metastasis of Tumor Cells Is Enhanced by Downregulation of Bit1 英文参考文献.docVIP

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Metastasis of Tumor Cells Is Enhanced by Downregulation of Bit1 英文参考文献.doc

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Metastasis of Tumor Cells Is Enhanced by Downregulation of Bit1 英文参考文献

MetastasisofTumorCellsIsEnhancedby DownregulationofBit1 PriyaPrakashKarmali1,ChrisBrunquell2,HauTram3,ShubhaKaleIreland3,ErkkiRuoslahti2 ,Hector Biliran3* 1Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America, 2Sanford-Burnham Medical Research Institute, Santa Barbara, California, UnitedStatesofAmerica,3DepartmentofBiology,XavierUniversityofLouisiana,NewOrleans,Louisiana,UnitedStatesofAmerica Abstract Background:Resistancetoanoikis,whichisdefinedasapoptosisinducedbylossofintegrin-mediatedcellattachmentto the extracellular matrix, is a determinant of tumor progression and metastasis. We have previously identified the mitochondrial Bit1 (Bcl-2 inhibitor of transcription) protein as a novel anoikis effector whose apoptotic function is independentfromcaspasesandisuniquelycontrolledbyintegrins.Inthisreport,weexaminedthepossibilitythatBit1is suppressedduringtumorprogressionandthatBit1downregulationmayplayaroleintumormetastasis. Methodology/PrincipalFindings:Usingahumanbreasttumortissuearray,wefoundthatBit1expressionissuppressedin a significant fraction of advanced stages of breast cancer. Targeted disruption of Bit1 via shRNA technology in lowly aggressiveMCF7cellsconferredenhancedanoikisresistance,adhesiveandmigratorypotential,whichcorrelatedwithan increaseinactiveExtracellularkinaseregulated(Erk)levelsandadecreaseinErk-directedphosphataseactivity.Thesepro- metastasis phenotypes were also observed following downregulation of endogenous Bit1 in Hela and B16F1 cancer cell lines.TheenhancedmigratoryandadhesivepotentialofBit1knockdowncellsisinpartdependentontheirhighlevelofErk activation since down-regulating Erk in these cells attenuated their enhanced motility and adhesive properties. The Bit1 knockdownpoolsalsoshowedastatisticallyhighlysignificantincreaseinexperimentallungmetastasis,withnodifferences intumorgrowthrelativetocontrolclonesinvivousingaBALB/cnudemousemodelsystem.Importantly,thepulmonary metastasesofBit1knockdowncellsexhi