2478 - Mitochondrial Proteins as Therapeutic Targets in Hepatocellular Carcinoma: Evidence from Mendelian Randomization Analysis
Presenter(s)
Y. Hong1, X. Zhang2, and J. Sui3; 1Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China, 2Department of Radiation Oncology, Chongqing Cancer Hospital & Cancer Institute, Chongqing, China, 3Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing,, Chongqing, China
Purpose/Objective(s): Hepatocellular carcinoma (HCC) is a main cause of cancer-related death, severely threatening public health. The pathogenesis of HCC is complicated, which remains to be comprehensively investigated, especially the roles of mitochondria. There is a consensus that mitochondria perform vital roles in multiple cancers, including HCC. However, the causal relationship between mitochondrial dysfunction and HCC is uncertain.To this end, we conducted this study to explore the complicated causal relationship between mitochondrial proteins and HCC risk by a two-sample MR analysis.
Materials/Methods:
Summary-level genome-wide association studies (GWAS) data for 64 mitochondrial proteins were obtained from the IEU GWAS database, and data for hepatocellular carcinoma (HCC) were sourced from the FinnGen database. A comprehensive two-sample Mendelian randomization (MR) analysis was employed to investigate the causal relationships between mitochondrial proteins and HCC. Multiple MR methods, including inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode, and simple mode, were applied to strengthen the causal inference. Furthermore, sensitivity analyses were conducted to assess the robustness of the findings. In vitro cell experiments were performed to provide additional validation of the results. .Results: The results of the MR analyses showed that 10 mitochondrial proteins were positively associated with HCC risk [p < 0.05, odds ratio (OR) >1], indicating their pro-tumorigenic effect; 15 mitochondrial proteins were negatively associated with HCC risk (p < 0.05, odds ratio (OR) <1), suggesting their anti-tumorigenic effect. The MR results’ reliability was confirmed by sensitivity analyses. Furthermore, cellular experiments demonstrated that MTRF1L, a molecule identified in our study with pro-tumorigenic properties, promotes cell proliferation and migration.
Conclusion: Our study revealed for the first time the causality of mitochondrial proteins and HCC. These findings not only verify the potential of targeting mitochondrial proteins therapy for HCC, but also lay a foundation for further research into the role of mitochondrial proteins in the initiation and development of HCC.