首页|Silencing MFN2 Drives WNT/β-catenin Nucleation to Reduce Sorafenib Sensitivity in Hepatocellular Carcinoma Cells
Silencing MFN2 Drives WNT/β-catenin Nucleation to Reduce Sorafenib Sensitivity in Hepatocellular Carcinoma Cells
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Objective:Mitofusin-2(MFN2)is a mitochondrial membrane protein that plays a critical role in regulating mitochondrial fusion and cellular metabolism.To further elucidate the impact of MFN2,this study aimed to investigate its significance on hepatocellular carcinoma(HCC)cell function and its potential role in mediating chemosensitivity.Methods:This study investigated the effects of silencing and overexpressing MFN2 on the survival,proliferation,invasion and migration abilities,and sorafenib resistance of MHCC97-L HCC cells.Additional experiments were conducted using XAV939(a β-catenin inhibitor)and HLY78(a β-catenin activator)to further validate these findings.Results:Silencing MFN2 significantly promoted the survival and proliferation of MHCC97-L cells,enhanced their invasion and migration capacities,increased the IC50 of sorafenib,reduced the percentage of TUNEL-positive cells,and decreased the expression of proapoptotic proteins.Additionally,silencing MFN2 markedly induced the nuclear translocation of β-catenin,increased β-catenin acetylation levels and enhanced the expression of the downstream regulatory proteins Snail 1 and Vimentin while inhibiting E-cadherin expression.Conversely,overexpressing MFN2 reversed the effects observed in MHCC97-L cells mentioned above.The results confirmed that silencing MFN2 activated the β-catenin/epithelial-mesenchymal transition(EMT)pathway and reduced the sensitivity of cells to sorafenib,which could be reversed by XAV939 treatment.Conversely,overexpression of MFN2 inhibited the β-catenin/EMT pathway and increased the sensitivity of cells to sorafenib,which could be altered by HLY78.Conclusion:Low expression of MFN2 in HCC cells promotes the nuclear translocation of β-catenin,thereby activating the EMT pathway and mediating resistance to sorafenib.
Department of Geriatric Medicine,Shengli Clinical Medical College of Fujian Medical University Fujian Key Laboratory of Geriatrics Diseases,Fujian Provincial Center for Geriatrics,Fujian Provincial Hospital,Fuzhou 350001,China
Department of Rehabilitation,Shengli Clinical Medical College of Fujian Medical University
Fujian Provincial Hospital,Fuzhou 350001,China
Department of Gynecology,Shengli Clinical Medical College of Fujian Medical University
Department of Ultrasonography,Shengli Clinical Medical College of Fujian Medical University
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Startup Fund for Scientific Research,Fujian Medical UniversityGuiyang Science and The Natural Science Foundation of Fujian Province(general program)
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