1. System biology analysis reveals the role of voltage-dependent anion channel in mitochondrial dysfunction during non-alcoholic fatty liver disease progression into hepatocellular carcinoma
- Author
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Xiang Wang, Qunxiang Ong, Miaoqing Zhao, Yanping Zhu, Jia Mi, Fuyi Xu, Chao Zhang, Geng Tian, Chunhua Yang, Wenguo Jiang, Xiuxiu Liu, Jonas Bergquist, Lu Lu, Shasha Li, and Ying Tan
- Subjects
0301 basic medicine ,Male ,Proteomics ,Cancer Research ,Proteome ,Tafazzin ,voltage-dependent anion channel ,Mitochondrion ,Transcriptome ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Cardiolipin ,Voltage-Dependent Anion Channels ,Gene Regulatory Networks ,Genetics, Genomics, and Proteomics ,system biology ,Fatty liver ,Liver Neoplasms ,Biochemistry and Molecular Biology ,General Medicine ,hepatocellular carcinoma ,Lipidome ,Middle Aged ,Mitochondria ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Original Article ,Disease Susceptibility ,VDAC1 ,Signal Transduction ,non‐alcoholic fatty liver disease ,Carcinoma, Hepatocellular ,Quantitative Trait Loci ,Biology ,03 medical and health sciences ,medicine ,Animals ,Humans ,mitochondria dysfunction ,Aged ,Neoplasm Staging ,Gene Expression Profiling ,Genetic Variation ,non-alcoholic fatty liver disease ,Original Articles ,medicine.disease ,digestive system diseases ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Tumor progression ,Cancer research ,biology.protein ,Neoplasm Grading ,voltage‐dependent anion channel ,Biokemi och molekylärbiologi - Abstract
Non‐alcoholic fatty liver disease (NAFLD) is one of the most common causes of hepatocellular carcinoma (HCC), but the underlying mechanisms behind the correlation of NAFLD with HCC are unclear. We aimed to uncover the genes and potential mechanisms that drive this progression. This study uncovered the genes and potential mechanisms through a multiple ’omics integration approach. Quantitative proteomics combined with phenotype‐association analysis was performed. To investigate the potential mechanisms, a comprehensive transcriptome/lipidome/phenome‐wide association analysis was performed in genetic reference panel BXD mice strains. The quantitative proteomics combined with phenotype‐association results showed that VDAC1 was significantly increased in tumor tissues and correlated with NAFLD‐related traits. Gene co‐expression network analysis indicated that VDAC1 is involved in mitochondria dysfunction in the tumorigenic/tumor progression. The association between VDAC1 and mitochondria dysfunction can be explained by the fact that VDAC1 was associated with mitochondria membrane lipids cardiolipin (CL) composition shift. VDAC1 was correlated with the suppression of mature specie CL(LLLL) and elevation level of nascent CL species. Such profiling shift was supported by the significant positive correlation between VDAC1 and PTPMT1, as well as negative correlation with CL remodeling enzyme Tafazzin (TAZ). This study confirmed that the expression of VADC1 was dysregulated in NAFLD‐driven HCC and associated with NAFLD progression. The VDAC1‐driven mitochondria dysfunction is associated with cardiolipin composition shift, which causes alteration of mitochondria membrane properties.
- Published
- 2020