The Study On Effect Of Simvastatin On Epithelial-mesenchymal Transition Of Ovarian Cancer And Endometrial Carcinoma Through SPAG9/JNK Pathway

Part one Effects of simvastatin on TGF-β induced epithelial-to-mesenchymal transition in ovarian cancerObjectiveTo investigate the effect of simvastatin on epithelial-to-mesenchymal transition(EMT)induced by transforming growth factor-β(TGF-(3)in ovarian cancer cells and to study the possible mechanism.MethodsThe ovarian cancer cells were divided into the control group,simvastatin group,TGF-P group,and simvastatin + TGF-β group.The effects of simvastatin and TGF-βat different concentrations on the cell proliferation was detected with CCK-8.The migration and invasion ability were assessed with wound healing assay and Transwell assay respectively.The changes of EMT and signaling pathway were determined with Western blotting.ResultsIn Skvo3 and A2780 cells,simvastatin reduced cell proliferation,while TGF-βpromoted cell proliferation,decreased cell migration and invasion,and reduced TGF-β-induced cell migration and invasion,and reversed EMT and TGF-β induced EMT.Further experiments showed that simvastatin could reduce the expression of sperm-associated antigen 9(SPAG9)/c-Jun N-terminal kinase(JNK)pathway and reverse TGF-β induced SPAG9/JNK pathway(P<0.05).ConclusionSimvastatin can reduce the proliferation,migration,invasion and EMT induced by TGF-β in ovarian cancer cells,possibly by regulating SPAG9/JNK pathway.Part two Simvastatin inhibits 17β-estradiol induced epithelial-mesenchymal transition via the SPAG9/JNK and ROCK/Par3 pathways in endometrial cancerObjectiveTo investigate the role of simvastatin in 17β-estradiol induced epithelial-mesenchymal transition(EMT)in endometrial cancer and further explore the potential mechanism underlying this effect.MethodsUsing two endometrial adenocarcinoma cell lines,Ishikawa cells and KLE cells,which were divided into the control group,simvastatin group,17β-estradiol group,simvastatin + 17β-estradiol group,and simvastatin + estrogen receptor inhibitor(ICI182,780)group.The effects of simvastatin and 17β-estradiol at different concentrations on the cell proliferation was detected with CCK-8.The migration and invasion ability were assessed with wound healing assay and Transwell assay respectively.The changes of EMT and the activity of Sperm-associated antigen 9(SPAG9)/Jun N-terminal kinase(JNK)and Rho-associated kinase(ROCK)/Par3(the polarity complex protein)signaling were determined with Western blotting.ResultsIn Ishikawa cells and KLE cells,simvastatin reduced cell proliferation,while 17β-estradiol promoted cell proliferation,Simvastatin decreased 17β-estradiol induced cell proliferation;Simvastatin decreased cell migration and invasion,and the treatment significantly reduced 17β-estradiol-induced cell migration and invasion in both cell lines.Simvastatin reversed EMT and 17β-estradiol induced EMT.Moreover,the effects of simvastatin could be incompletely abolished by ICI 182,780,a specific estrogen receptor(ER)inhibitor,in Ishikawa cells.In addition,further experiments showed that simvastatin reduced the expression of SPAG9/JNK pathway and reversed 17(3-estradiol induced SPAG9/JNK pathway,decreased ROCK expression and increased Par3 expression and reversed 17β-estradiol induced ROCK/Par3 pathway in both cell lines.However,ICI 182,780 only showed an inhibition effect with simvastatin to two pathways in Ishikawa cells.ConclusionSimvastatin abolishes 17β-estradiol induced cell proliferation,migration.invasion and EMT in endometrial adenocarcinoma cells,possibly by regulating SPAG9/JNK signaling and the ROCK/Par3 pathway.The effect of simvastatin could be partially abolished using an ER inhibitor,only in ER-positive cells.Our study provides novel mechanistic insights into the anti-tumor effects of simvastatin,suggesting that statins may be a promising treatment strategy for advanced endometrial cancer.