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TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is a common malignancy. Despite progress in treatment, HCC is still one of the most lethal cancers. Therefore, deepening molecular mechanisms underlying HCC pathogenesis and development is required to uncover new therapeutic strategies. Metabolic reprogramming is emerging as a critical player in promoting tumor survival and proliferation to sustain increased metabolic needs of cancer cells. Among the metabolic pathways, the tricarboxylic acid (TCA) cycle is a primary route for bioenergetic, biosynthetic, and redox balance requirements of cells. In recent years, a large amount of evidence has highlighted the relevance of the TCA cycle rewiring in a variety of cancers. Indeed, aberrant gene expression of several key enzymes and changes in levels of critical metabolites have been observed in many solid human tumors. In this review, we summarize the role of the TCA cycle rewiring in HCC by reporting gene expression and activity dysregulation of enzymes relating not only to the TCA cycle but also to glutamine metabolism, malate/aspartate, and citrate/pyruvate shuttles. Regarding the transcriptional regulation, we focus on the link between NF-?B-HIF1 transcriptional factors and TCA cycle reprogramming. Finally, the potential of metabolic targets for new HCC treatments has been explored.

SUBMITTER: Todisco S

PROVIDER: S-EPMC7016696 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma.

Todisco Simona S Convertini Paolo P Iacobazzi Vito V Infantino Vittoria V

Cancers 20191225 1

Hepatocellular carcinoma (HCC) is a common malignancy. Despite progress in treatment, HCC is still one of the most lethal cancers. Therefore, deepening molecular mechanisms underlying HCC pathogenesis and development is required to uncover new therapeutic strategies. Metabolic reprogramming is emerging as a critical player in promoting tumor survival and proliferation to sustain increased metabolic needs of cancer cells. Among the metabolic pathways, the tricarboxylic acid (TCA) cycle is a prima ...[more]

PMID: 31881713

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Project description:Background Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Cuproptosis is a newly defined form of cell death. Copper ion induces cell death by binding to the tricarboxylic acid cycle (TCA). The effect of cuproptosis-related and TCA-related genes on the clinical prognosis of HCC is still unclear. In this study, we explores the genetic changes of cuproptosis-related genes that affect the TCA process and their potential therapeutic value in HCC patients. Methods The cuproptosis and TCA-related genes were obtained from cuproptosis-related articles and the molecular signatures database. The prognosis signatures of eight related genes were constructed using the last absolute shrinkage and selection operator (LASSO), and Receiver Operating Characteristic (ROC) curves were used to evaluate the signature. In addition, we analyzed downstream functional enrichment and immune infiltration to explore cuproptosis-inducing drugs and immunotherapeutic responses. All these analyses were validated using multiple datasets of the International Cancer Genome Consortium (ICGC). Results TCA and copper malnutrition-related genes (CDKN2A, IDH1, OGDHL, IDH3G, IDH3B, GLS, DLAT, LIPT1) were finally included. According to the risk score, they were divided into high-risk and low-risk groups. Survival analysis showed that the overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. We established a risk prognostic feature to predict the OS of patients with HCC. Based on this feature and the clinical stage, we constructed a nomogram. Functional enrichment analysis revealed pathways related to organelle division and the cell cycle. Different risk scores had different immune abundances in immune cells (including macrophages and regulatory T-cells) and immune pathways (including antigen-presenting cells co-stimulation). Moreover, the drug sensitivity of eleschomol and PD-L1 in the high-risk group was better than that in the low-risk group. The status of TP53 somatic mutation was also closely related to the risk score. Conclusion In this study, we established a new prediction signature of eight genes related to cuproptosis and the TCA process, which can effectively predict the prognosis of HCC patients.

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TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma.

Publications

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma.

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