ArticleProceedings of the National Academy of Sciences of the United States of America2018
Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers.
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Who cites it
131 citing papers in PubMed.
- Lipid droplet-associated gene signatures classify metabolic subtypes and identify PLIN3 as a key driver in hepatocellular carcinoma.Genes & diseases · 2026Article
- Sulfur amino acid restriction prevents S-adenosylmethionine-driven liver steatosis, hepatocellular carcinoma, and metabolic remodeling in high-fat-fed GNMT-null mice.bioRxiv : the preprint server for biology · 2026Article
- Loss of hepatocyte PI3Kα reduces hepatocellular carcinoma and hepatocyte proliferation in association with altered lipid metabolism.JHEP reports : innovation in hepatology · 2026Article
- Metabotropic Glutamate Receptor 3 Expression During Liver Disease Progression: Association with Inflammation and Cell Viability in Hepatocellular Carcinoma.International journal of molecular sciences · 2026Article
- MAGMDA: a multi-order adaptive graph-based miRNA-disease association prediction model.BMC bioinformatics · 2026Article
- Integrated multi-omics analysis reveals comprehensive metabolism-driven tumor heterogeneity and immune microenvironment in hepatocellular carcinomas.Scientific reports · 2026Article
- Metabolic reprogramming in cancer: signaling pathways and therapeutic targets.Molecular cancer · 2026Review
- Integrative multi-omics analysis proposes a metabolic classification of gliomas: distinct metabolic states, immune infiltration, and prognosis.Journal of translational medicine · 2025Article
- Molecular subtypes of hepatocellular carcinoma linked to liver cell lineages and clinical outcomes of combination immunotherapy.Cell reports. Medicine · 2025Article
- Aldolase a in pan-cancer and lung squamous cell carcinoma: prognostic value and macrophage-driven immune suppression unveiled by multi-omics and cohort validation.Cancer cell international · 2025Article
- Intratumoral microbial heterogeneity in HCC reveals a potential therapeutic target.JHEP reports : innovation in hepatology · 2025Article
- Proteomic subtyping highlights tumor heterogeneity of human HCC.Virchows Archiv : an international journal of pathology · 2025Article
- Loss of glomerular aldolase B in diabetic nephropathy promotes renal fibrosis via activating Akt/GSK/β-catenin axis.Journal of advanced research · 2025Article
- YULINK deficiency promotes cell death under glucose restriction in HCC cells in association with GLUT1-mediated glycolysis.Molecular medicine (Cambridge, Mass.) · 2025Article
- Metabolic genes interaction perturbation network identified and validated CD24 as a novel prognostic gene in hepatocellular carcinoma.Discover oncology · 2025Article
- Comprehensive analysis of immune subtype characterization on identification of potential cells and drugs to predict response to immune checkpoint inhibitors for hepatocellular carcinoma.Genes & diseases · 2025Article
- Prediagnostic Plasma Metabolites Are Associated with Incident Hepatocellular Carcinoma: A Prospective Analysis.Cancer prevention research (Philadelphia, Pa.) · 2025Article
- Hepatocellular carcinoma: signaling pathways and therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Heterogeneity in polyamine metabolism dictates prognosis and immune checkpoint blockade response in hepatocellular carcinoma.Frontiers in immunology · 2025Article
- Interactions between the metabolic reprogramming of liver cancer and tumor microenvironment.Frontiers in immunology · 2025Review
71 more citing papers are in PubMed but not listed here.
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8 authors.
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Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent forms of liver cancer, and effective treatment methods are limited due to tumor heterogeneity. There is a great need for comprehensive approaches to stratify HCC patients, gain biological insights into subtypes, and ultimately identify effective therapeutic targets. We stratified HCC patients and characterized each subtype using transcriptomics data, genome-scale metabolic networks and network topology/controllability analysis. This comprehensive systems-level analysis identified three distinct subtypes with substantial differences in metabolic and signaling pathways reflecting at genomic, transcriptomic, and proteomic levels. These subtypes showed large differences in clinical survival associated with altered kynurenine metabolism, WNT/β-catenin-associated lipid metabolism, and PI3K/AKT/mTOR signaling. Integrative analyses indicated that the three subtypes rely on alternative enzymes (e.g., ACSS1/ACSS2/ACSS3, PKM/PKLR, ALDOB/ALDOA, MTHFD1L/MTHFD2/MTHFD1) to catalyze the same reactions. Based on systems-level analysis, we identified 8 to 28 subtype-specific genes with pivotal roles in controlling the metabolic network and predicted that these genes may be targeted for development of treatment strategies for HCC subtypes by performing in silico analysis. To validate our predictions, we performed experiments using HepG2 cells under normoxic and hypoxic conditions and observed opposite expression patterns between genes expressed in high/moderate/low-survival tumor groups in response to hypoxia, reflecting activated hypoxic behavior in patients with poor survival. In conclusion, our analyses showed that the heterogeneous HCC tumors can be stratified using a metabolic network-driven approach, which may also be applied to other cancer types, and this stratification may have clinical implications to drive the development of precision medicine.
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