Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer 英文参考文献.docVIP

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Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer 英文参考文献.doc

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Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer 英文参考文献

o PL SMEDICINE DysfunctionalKEAP1–NRF2Interaction inNon-Small-CellLungCancer Anju Singh1,Vikas Misra1,Rajesh K.Thimmulappa1,Hannah Lee1,Stephen Ames2,Mohammad O.Hoque3, James G.Herman2,Stephen B.Baylin2,David Sidransky2,3,Edward Gabrielson2,Malcolm V.Brock2,Shyam Biswal1,2,4* 1DepartmentofEnvironmentalHealthSciences,BloombergSchoolofPublicHealth,JohnsHopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica,2Department ofOncology,SidneyKimmelComprehensiveCancerCenter,JohnsHopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica,3DepartmentofOtolaryngology— HeadandNeckSurgery,JohnsHopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica,4DivisionofPulmonaryandCriticalCareMedicine,SchoolofMedicine, JohnsHopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica Funding:Thisworkwassupported byNationalInstitutesofHealth grantsP50CA058184(SBB), ABSTRACT HL081205(SB),andP30ES038819 andbyaYoungClinicalScientist AwardfromtheFlightAttendant MedicalResearchInstitute(SB).The fundershadnoroleinstudydesign, datacollectionandanalysis,decision topublish,orpreparationofthe manuscript. Background Nuclearfactorerythroid-2relatedfactor2(NRF2)isaredox-sensitivetranscriptionfactorthat positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidantsandxenobioticdetoxificationenzymeshasbeenimplicatedinresistanceoftumor cellsagainstchemotherapeuticdrugs. CompetingInterests:Theauthors havedeclaredthatnocompeting interestsexist. AcademicEditor:Matthew Meyerson,Dana-FarberCancer Institute,UnitedStatesofAmerica MethodsandFindings HerewereportasystematicanalysisoftheKEAP1genomiclocusinlungcancerpatientsand cell lines that revealed deletion, insertion, and missense mutation