MTFR2-dependent mitochondrial fission promotes HCC progression
Abstract Background The role of mitochondrial dynamics, encompassing fission, fusion, and mitophagy, in cancer progression has been extensively studied. However, the specific impact of mitochondrial dynamics on hepatocellular carcinoma (HCC) is still under investigation. Methods In this study, mitoc...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-023-04845-6 |
| _version_ | 1797349739739480064 |
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| author | La Zhang Xiuzhen Zhang Haichuan Liu Changhong Yang Jiyao Yu Wei Zhao Jiao Guo Baoyong Zhou Ning Jiang |
| author_facet | La Zhang Xiuzhen Zhang Haichuan Liu Changhong Yang Jiyao Yu Wei Zhao Jiao Guo Baoyong Zhou Ning Jiang |
| author_sort | La Zhang |
| collection | DOAJ |
| description | Abstract Background The role of mitochondrial dynamics, encompassing fission, fusion, and mitophagy, in cancer progression has been extensively studied. However, the specific impact of mitochondrial dynamics on hepatocellular carcinoma (HCC) is still under investigation. Methods In this study, mitochondrial dynamic genes were obtained from the MitoCarta 3.0 database, and gene expression data were collected from The Cancer Genome Atlas (TCGA) database. Based on the expression of these dynamic genes and differentially expressed genes (DEGs), patients were stratified into two clusters. Subsequently, a prognostic model was constructed using univariate COX regression and the least absolute shrinkage and selection operator (LASSO) regression, and the prognostic signature was evaluated. We analyzed the interaction between these model genes and dynamic genes to identify hub genes and reveal mitochondrial status. Furthermore, we assessed immune infiltration, tumor mutational burden (TMB), tumor stemness indices (TSI), and the response to immune checkpoint block (ICB) therapy using the TIDE algorithm and risk scores. Additionally, transmission electron microscopy (TEM), hematoxylin-eosin (H&E) staining, immunohistochemistry (IHC), western blotting (WB), and immunofluorescence (IF) were conducted to afford detailed visualization of the morphology of the mitochondria and the expression patterns of fission-associated proteins. Results Patients in Cluster 2 exhibited heightened mitochondrial fission and had a worse prognosis. The up-regulated dynamic genes in Cluster 2 were identified as fission genes. GO/KEGG analyses reconfirmed the connection of Cluster 2 to augmented mitochondrial fission activities. Subsequently, a ten-gene prognostic signature based on the differentially expressed genes between the two clusters was generated, with all ten genes being up-regulated in the high-risk group. Moreover, the potential links between these ten signature genes and mitochondrial dynamics were explored, suggesting their involvement in mediating mitochondrial fission through interaction with MTFR2. Further investigation revealed that the high-risk group had an unfavorable prognosis, with a higher mutation frequency of TP53, increased immune checkpoint expression, a higher TIS score, and a lower TIDE score. The mitochondrial imbalance characterized by increased fission and upregulated MTFR2 and DNM1L expression was substantiated in both HCC specimens and cell lines. Conclusions In conclusion, we developed a novel MTFR2-related prognostic signature comprising ten mitochondrial dynamics genes. These genes play crucial roles in mitochondrial fission and have the potential to serve as important predictors and therapeutic targets for HCC. |
| first_indexed | 2024-03-08T12:34:46Z |
| format | Article |
| id | doaj.art-c059a2324947432c81f8db2aaf881b57 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-08T12:34:46Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-c059a2324947432c81f8db2aaf881b572024-01-21T12:33:04ZengBMCJournal of Translational Medicine1479-58762024-01-0122111810.1186/s12967-023-04845-6MTFR2-dependent mitochondrial fission promotes HCC progressionLa Zhang0Xiuzhen Zhang1Haichuan Liu2Changhong Yang3Jiyao Yu4Wei Zhao5Jiao Guo6Baoyong Zhou7Ning Jiang8Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical UniversitySchool of Basic Medical Science, Chongqing Medical UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Bioinformatics, Chongqing Medical UniversityThe Second Clinical College of Chongqing Medical UniversitySchool of Basic Medical Science, Chongqing Medical UniversitySchool of Basic Medical Science, Chongqing Medical UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Pathology, School of Basic Medical Science, Chongqing Medical UniversityAbstract Background The role of mitochondrial dynamics, encompassing fission, fusion, and mitophagy, in cancer progression has been extensively studied. However, the specific impact of mitochondrial dynamics on hepatocellular carcinoma (HCC) is still under investigation. Methods In this study, mitochondrial dynamic genes were obtained from the MitoCarta 3.0 database, and gene expression data were collected from The Cancer Genome Atlas (TCGA) database. Based on the expression of these dynamic genes and differentially expressed genes (DEGs), patients were stratified into two clusters. Subsequently, a prognostic model was constructed using univariate COX regression and the least absolute shrinkage and selection operator (LASSO) regression, and the prognostic signature was evaluated. We analyzed the interaction between these model genes and dynamic genes to identify hub genes and reveal mitochondrial status. Furthermore, we assessed immune infiltration, tumor mutational burden (TMB), tumor stemness indices (TSI), and the response to immune checkpoint block (ICB) therapy using the TIDE algorithm and risk scores. Additionally, transmission electron microscopy (TEM), hematoxylin-eosin (H&E) staining, immunohistochemistry (IHC), western blotting (WB), and immunofluorescence (IF) were conducted to afford detailed visualization of the morphology of the mitochondria and the expression patterns of fission-associated proteins. Results Patients in Cluster 2 exhibited heightened mitochondrial fission and had a worse prognosis. The up-regulated dynamic genes in Cluster 2 were identified as fission genes. GO/KEGG analyses reconfirmed the connection of Cluster 2 to augmented mitochondrial fission activities. Subsequently, a ten-gene prognostic signature based on the differentially expressed genes between the two clusters was generated, with all ten genes being up-regulated in the high-risk group. Moreover, the potential links between these ten signature genes and mitochondrial dynamics were explored, suggesting their involvement in mediating mitochondrial fission through interaction with MTFR2. Further investigation revealed that the high-risk group had an unfavorable prognosis, with a higher mutation frequency of TP53, increased immune checkpoint expression, a higher TIS score, and a lower TIDE score. The mitochondrial imbalance characterized by increased fission and upregulated MTFR2 and DNM1L expression was substantiated in both HCC specimens and cell lines. Conclusions In conclusion, we developed a novel MTFR2-related prognostic signature comprising ten mitochondrial dynamics genes. These genes play crucial roles in mitochondrial fission and have the potential to serve as important predictors and therapeutic targets for HCC.https://doi.org/10.1186/s12967-023-04845-6Hepatocellular carcinomaMitochondrial dynamicsFissionPrognostic modelMTFR2 |
| spellingShingle | La Zhang Xiuzhen Zhang Haichuan Liu Changhong Yang Jiyao Yu Wei Zhao Jiao Guo Baoyong Zhou Ning Jiang MTFR2-dependent mitochondrial fission promotes HCC progression Journal of Translational Medicine Hepatocellular carcinoma Mitochondrial dynamics Fission Prognostic model MTFR2 |
| title | MTFR2-dependent mitochondrial fission promotes HCC progression |
| title_full | MTFR2-dependent mitochondrial fission promotes HCC progression |
| title_fullStr | MTFR2-dependent mitochondrial fission promotes HCC progression |
| title_full_unstemmed | MTFR2-dependent mitochondrial fission promotes HCC progression |
| title_short | MTFR2-dependent mitochondrial fission promotes HCC progression |
| title_sort | mtfr2 dependent mitochondrial fission promotes hcc progression |
| topic | Hepatocellular carcinoma Mitochondrial dynamics Fission Prognostic model MTFR2 |
| url | https://doi.org/10.1186/s12967-023-04845-6 |
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