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Silencing MFN2 Drives WNT/β-catenin Nucleation to Reduce Sorafenib Sensitivity in Hepatocellular Carcinoma Cells
Chai-Ming Zeng1, Bin Shao2, Yan-Ping Chen3
1Department 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.
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 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 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.
Insights
Low mitofusin-2 (MFN2) expression in liver cancer cells promotes tumor growth and resistance to sorafenib by activating the beta-catenin/EMT pathway. Restoring MFN2 enhances chemosensitivity.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Mitofusin-2 (MFN2) is a mitochondrial protein crucial for mitochondrial fusion and cellular metabolism.
- Its role in hepatocellular carcinoma (HCC) pathogenesis and chemosensitivity remains to be fully elucidated.
Purpose of the Study:
- To investigate the impact of MFN2 on HCC cell function, including survival, proliferation, invasion, and migration.
- To determine MFN2's role in mediating sensitivity or resistance to sorafenib treatment in HCC.
Main Methods:
- Silencing and overexpression of MFN2 in MHCC97-L HCC cells.
- Assessment of cell viability, proliferation, invasion, migration, and apoptosis.
- Analysis of the beta-catenin pathway, epithelial-mesenchymal transition (EMT) markers, and sorafenib resistance.
- Pharmacological modulation of beta-catenin using XAV939 and HLY78.
Main Results:
- MFN2 silencing enhanced HCC cell survival, proliferation, invasion, and migration, while increasing sorafenib resistance.
- MFN2 silencing induced beta-catenin nuclear translocation, increased acetylation, and promoted EMT.
- MFN2 overexpression reversed these effects, inhibiting EMT and enhancing sorafenib sensitivity.
- The beta-catenin/EMT pathway was confirmed as a mediator of MFN2's effects on HCC cell function and chemosensitivity.
Conclusions:
- Reduced MFN2 expression in HCC promotes tumor progression and sorafenib resistance.
- This occurs via activation of the beta-catenin/EMT pathway.
- MFN2 modulation offers a potential therapeutic strategy for improving HCC treatment outcomes.
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