Silencing MFN2 Drives WNT/β-catenin Nucleation to Reduce Sorafenib Sensitivity in Hepatocellular Carcinoma Cells  

作　　者：Chai-ming ZENG Bin SHAO Yan-ping CHEN Gui-sheng DING 

机构地区：[1]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 [2]Department of Rehabilitation,Shengli Clinical Medical College of Fujian Medical University,Fujian Provincial Hospital,Fuzhou,350001,China [3]Department of Gynecology,Shengli Clinical Medical College of Fujian Medical University,Fujian Provincial Hospital,Fuzhou,350001,China [4]Department of Ultrasonography,Shengli Clinical Medical College of Fujian Medical University,Fujian Provincial Hospital,Fuzhou,350001,China

出　　处：《Current Medical Science》2024年第4期789-798,共10页当代医学科学（英文）

基　　金：supported by Startup Fund for Scientific Research,Fujian Medical University(No.2019QH1146);Guiyang Science and The Natural Science Foundation of Fujian Province(general program)(No.2020J011061).

摘　　要：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(aβ-catenin inhibitor)and HLY78(aβ-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 ofβ-catenin,increasedβ-catenin acetylation levels and enhanced the expression of the downstream regulatory proteins Snail1 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 theβ-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 theβ-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 ofβ-catenin,thereby activating the EMT pathway and mediating resistance to sorafenib.

关 键 词：mitofusin-2 epithelial-mesenchymal transition sorafenib resistance apoptosis hepatocellular carcinoma 

分 类 号：R735.7[医药卫生—肿瘤]