System biology analysis reveals the role of voltage‐dependent anion channel in mitochondrial dysfunction during non‐alcoholic fatty liver disease progression into hepatocellular carcinoma

• Published in: Cancer science Vol. 111; no. 11; pp. 4288 - 4302
• Main Authors: Zhu, Yanping, Zhang, Chao, Xu, Fuyi, Zhao, Miaoqing, Bergquist, Jonas, Yang, Chunhua, Liu, Xiuxiu, Tan, Ying, Wang, Xiang, Li, Shasha, Jiang, Wenguo, Ong, Qunxiang, Lu, Lu, Mi, Jia, Tian, Geng
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.11.2020; John Wiley and Sons Inc
• Subjects: Aged; Animals; Association analysis; Carcinoma, Hepatocellular - diagnosis; Carcinoma, Hepatocellular - etiology; Cardiolipin; Diphosphatidylglycerol; Disease Models, Animal; Disease Susceptibility; Fatty liver; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genetic analysis; Genetic Variation; Hepatocellular carcinoma; Humans; Lipids; Liver cancer; Liver diseases; Liver Neoplasms - diagnosis; Liver Neoplasms - etiology; Male; Mice; Middle Aged; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; mitochondria dysfunction; Neoplasm Grading; Neoplasm Staging; non-alcoholic fatty liver disease; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Original; Peptides; Phenotypes; Proteins; Proteome; Proteomics; Proteomics - methods; Quantitative Trait Loci; Sample size; Signal Transduction; system biology; Tumorigenesis; voltage-dependent anion channel; Voltage-Dependent Anion Channels - genetics; Voltage-Dependent Anion Channels - metabolism; system biology; voltage-dependent anion channel; mitochondria dysfunction; non-alcoholic fatty liver disease; hepatocellular carcinoma
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.14651

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.