MTFR2-dependent mitochondrial fission promotes HCC progression

作者全名："Zhang, La; Zhang, Xiuzhen; Liu, Haichuan; Yang, Changhong; Yu, Jiyao; Zhao, Wei; Guo, Jiao; Zhou, Baoyong; Jiang, Ning"

作者地址："[Zhang, La; Liu, Haichuan; Zhou, Baoyong] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Chongqing, Peoples R China; [Zhang, Xiuzhen; Zhao, Wei; Guo, Jiao] Chongqing Med Univ, Sch Basic Med Sci, Chongqing, Peoples R China; [Yang, Changhong] Chongqing Med Univ, Dept Bioinformat, Chongqing, Peoples R China; [Yu, Jiyao] Chongqing Med Univ, Second Clin Coll, Chongqing, Peoples R China; [Jiang, Ning] Chongqing Med Univ, Sch Basic Med Sci, Dept Pathol, Chongqing, Peoples R China; [Jiang, Ning] Chongqing Med Univ, Mol Med Diagnost & Testing Ctr, Chongqing, Peoples R China; [Jiang, Ning] Chongqing Med Univ, Dept Pathol, Affiliated Hosp 1, Chongqing, Peoples R China"

通信作者："Zhou, BY (通讯作者)，Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Chongqing, Peoples R China.; Jiang, N (通讯作者)，Chongqing Med Univ, Sch Basic Med Sci, Dept Pathol, Chongqing, Peoples R China.; Jiang, N (通讯作者)，Chongqing Med Univ, Mol Med Diagnost & Testing Ctr, Chongqing, Peoples R China.; Jiang, N (通讯作者)，Chongqing Med Univ, Dept Pathol, Affiliated Hosp 1, Chongqing, Peoples R China."

来源：JOURNAL OF TRANSLATIONAL MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001145439400004

JCR分区：Q1

影响因子：7.4

年份：2024

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Hepatocellular carcinoma; Mitochondrial dynamics; Fission; Prognostic model; MTFR2

摘要："BackgroundThe 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.MethodsIn 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.ResultsPatients 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.ConclusionsIn 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."

基金机构：National Natural Science Foundation of China

基金资助正文："The authors would like to thank for Servier Medical Art, because the Fig. 1A was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license."