Alternative splicing: a bridge connecting NAFLD and HCC

Xu, Kequan; Wu, Taihu; Xia, Peng; Chen, Xi; Yua, Yuan

doi:10.1016/j.molmed.2023.07.001

Cited by 5 publications

(3 citation statements)

References 89 publications

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“…Due to the escalating prevalence of obesity and weight-related metabolic complications, NAFLD has become the most prevalent chronic liver ailment worldwide (41). In a subset of patients, hepatic steatosis progresses to NASH and may further develop into fibrosis, cirrhosis, and NAFLD-related HCC (42)(43)(44). Fatty acid metabolic reprogramming unique to hepatocytes is a key indicator of the liver cancer (45).…”

Section: Discussionmentioning

confidence: 99%

Unveiling the role of disulfidptosis-related genes in the pathogenesis of non-alcoholic fatty liver disease

Luo,

Guo,

Deng

et al. 2024

Front. Immunol.

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BackgroundsNon-alcoholic fatty liver disease (NAFLD) presents as a common liver disease characterized by an indistinct pathogenesis. Disulfidptosis is a recently identified mode of cell death. This study aimed to investigate the potential role of disulfidptosis-related genes (DRGs) in the pathogenesis of NAFLD.MethodsGene expression profiles were obtained from the bulk RNA dataset GSE126848 and the single-cell RNA dataset GSE136103, both associated with NAFLD. Our study assessed the expression of DRGs in NAFLD and normal tissues. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were employed to identify the key NAFLD-specific differentially expressed DRGs (DE-DRGs). To explore the biological functions and immune regulatory roles of these key DE-DRGs, we conducted immune infiltration analysis, functional enrichment analysis, consensus clustering analysis, and single-cell differential state analysis. Finally, we validated the expression and biological functions of DRGs in NAFLD patients using histology and RNA-sequencing transcriptomic assays with human liver tissue samples.ResultsThrough the intersection of WGCNA, differentially expressed genes, and DRGs, two key DE-DRGs (DSTN and MYL6) were identified. Immune infiltration analysis indicated a higher proportion of macrophages, T cells, and resting dendritic cells in NAFLD compared to control liver samples. Based on the key DE-DRGs, Two disulfidptosis clusters were defined in GSE126848. Cluster 1, with higher expression of the key DE-DRGs, exhibited increased immune infiltration abundance and was closely associated with oxidative stress and immune regulation compared to cluster 2. High-resolution analysis of mononuclear phagocytes highlighted the potential role of MYL6 in intrahepatic M1 phenotype Kupffer cells in NAFLD patients. Our transcriptome data revealed that the expression levels of the majority of DRGs were significantly increased in NAFLD patients. NAFLD patients exhibit elevated MYL6 correlating with inflammation, oxidative stress, and disease severity, offering promising diagnostic specificity.ConclusionThis comprehensive study provides evidence for the association between NAFLD and disulfidptosis, identifying potential target genes and pathways in NAFLD. The identification of MYL6 as a possible treatment target for NAFLD provided a novel understanding of the disease’s development.

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Section: Discussionmentioning

confidence: 99%

Unveiling the role of disulfidptosis-related genes in the pathogenesis of non-alcoholic fatty liver disease

Luo,

Guo,

Deng

et al. 2024

Front. Immunol.

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“… 22 , 23 It has been reported that selective splicing of RNA can regulate lipid metabolism, thereby preventing the onset of HCC. 24 Additionally, research has identified lipid metabolism-related gene markers that can be utilized to predict the prognosis of HCC. 25 Given the significance of lipid metabolism in malignant tumors, a comprehensive understanding of how lipid metabolism is reprogrammed in HCC could provide valuable insights into targeting metabolic networks within HCC.…”

Section: Introductionmentioning

confidence: 99%

Lipid Metabolism as a Potential Target of Liver Cancer

Wu,

Lin

2024

JHC

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Hepatocellular carcinoma (HCC) stands as a severe malignant tumor with a profound impact on overall health, often accompanied by an unfavorable prognosis. Despite some advancements in the diagnosis and treatment of this disease, improving the prognosis of HCC remains a formidable challenge. It is noteworthy that lipid metabolism plays a pivotal role in the onset, development, and progression of tumor cells. Existing research indicates the potential application of targeting lipid metabolism in the treatment of HCC. This review aims to thoroughly explore the alterations in lipid metabolism in HCC, offering a detailed account of the potential advantages associated with innovative therapeutic strategies targeting lipid metabolism. Targeting lipid metabolism holds promise for potentially enhancing the prognosis of HCC.

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“…[2][3][4][5][6][7][8] Research has demonstrated that the development of HCC is governed by intricate genetic and epigenetic mechanisms, in which abnormal RNA modifications play a pivotal role in causing variations in gene expression, thereby influencing the occurrence and progression of HCC. [9][10][11][12][13][14][15] Methylation involves a complex and dynamically reversible series of structural alterations induced by various enzymes. The discovery of N6-methyladenosine (m6A) has sparked interest in understanding its biological significance.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Divergent Gene Expression Landscapes of m6A/m5C/m1A Methylation Regulators in Hepatocellular Carcinoma Through Single-Cell and Bulk RNA Transcriptomic Analysis

Liu,

Rau,

Liu

et al. 2023

JHC

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RNA modifications mediated by the m6A, m1A, and m5C regulatory genes are crucial for the progression of malignancy. This study aimed to explore the expression of regulator genes for m6A/m5C/m1A methylation at the single-cell level and to validate their expression in cancerous and adjacent para-cancerous liver tissues of adult patients with HCC who underwent tumor resection. Methods: The bulk sequencing from The Cancer Genome Atlas (TCGA) database and the single-cell RNA sequencing (scRNA-seq) data obtained from the Gene Expression Omnibus (GEO) database were used to identify the dysregulated m6A/m5C/m1A genes for hepatocellular carcinoma (HCC). A real-time polymerase chain reaction (real-time PCR) was used to measure the expression of dysregulated m6A/m5C/m1A genes in collected human HCC tissues and compared with adjacent para-cancerous liver tissues. Immune cell infiltration with these significantly expressed methylation-related genes was evaluated using Timer2.0. Results: A discrepancy in m6A/m5C/m1A gene expression was observed between bulk sequencing and scRNA-seq. The clustered heatmap of the scRNA-seq-identified dysregulated m6A/m5C/m1A genes in TCGA cohort revealed heterogeneous expression of these methylation regulators within the cancer, whereas their expression in the adjacent liver tissues was more homogeneous. The real-time PCR validated the significant overexpression of DNMT1, NSUN5, TRMT6, IGF2BP1, and IGFBP3, which were identified using scRNA-seq, and IGFBP2, which was identified using bulk sequencing. These dysregulated methylation genes are mainly correlated with the infiltration of natural killer cells. Discussion: This study suggests that cellular diversity inside tumors contributes to the discrepancy in the expression of methylation regulator genes between traditional bulk sequencing and scRNA-seq. This study identified five regulatory genes that will be the focus of further studies regarding the function of m6A/m5C/m1A in HCC.

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Alternative splicing: a bridge connecting NAFLD and HCC

Cited by 5 publications

References 89 publications

Unveiling the role of disulfidptosis-related genes in the pathogenesis of non-alcoholic fatty liver disease

Unveiling the role of disulfidptosis-related genes in the pathogenesis of non-alcoholic fatty liver disease

Lipid Metabolism as a Potential Target of Liver Cancer

Deciphering the Divergent Gene Expression Landscapes of m6A/m5C/m1A Methylation Regulators in Hepatocellular Carcinoma Through Single-Cell and Bulk RNA Transcriptomic Analysis

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