Progesterone Inhibits Epithelial-to-Mesenchymal Transition in Endometrial Cancer 英文参考文献.docVIP

ProgesteroneInhibitsEpithelial-to-Mesenchymal TransitioninEndometrialCancer PaulH.vanderHorst1*,YongyiWang1,IngridVandenput2,LiesbethC.Ku¨hne1,PatriciaC.Ewing3, WilfredF.J.vanIJcken4,MartenvanderZee1,FredericAmant2,CurtW.Burger1,LeenJ.Blok1 1DepartmentofObstetricsandGynaecology,ErasmusUniversityMedicalCenterRotterdam,Rotterdam,TheNetherlands,2DivisionGynecologicOncology,University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium, 3Department of Pathology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands,4DepartmentofBiomics,ErasmusUniversityMedicalCenterRotterdam,Rotterdam,TheNetherlands Abstract Background: Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spreadofendometrialcancer:bystimulatingT-cellinfiltrationandbyinhibitingepithelial-to-mesenchymalcelltransition (EMT). MethodologyandPrincipalFindings:Paraffinsectionsfrompatientswith(n=9)orwithout(n=9)progressiveendometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory)T-lymphocytesandPRexpression.Progressivediseasewasobservedtobeassociatedwithsignificantlossof TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulationofpathwaysinvolvedinimmunesurveillance,EMTandmetastasis.Foranumberofgenes,suchasCXCL14,DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa(IK) endometrial cancer cell lines stably transfected withPRA(IKPRA),PRB(IKPRB)andPRA+PRB(IKPRAB)wereculturedinpresence/absenceofprogesterone(MPA)andusedf