Dataset Information

Metabolic Reprogramming and Its Relationship to Survival in Hepatocellular Carcinoma.

ABSTRACT: Hepatocarcinogenesis is frequently accompanied by substantial metabolic reprogramming to maximize the growth and proliferation of cancer cells. In this study, we carried out a comprehensive study of metabolomics and lipidomics profiles combined with gene expression analysis to characterize the metabolic reprogramming in hepatocellular carcinoma (HCC). Compared with adjacent noncancerous liver tissue, the enhanced aerobic glycolysis and de novo lipogenesis (DNL) and the repressed urea cycle were underscored in HCC tissue. Furthermore, multiscale embedded correlation analysis was performed to construct differential correlation networks and reveal pathologically relevant molecule modules. The obtained hub nodes were further screened according to the maximum biochemical diversity and the least intraclass correlation. Finally, a panel of ornithine, FFA 18:1, PC O-32:1 and TG (18:1_17:1_18:2) was generated to achieve the prognostic risk stratification of HCC patients (p < 0.001 by log-rank test). Altogether, our findings suggest that the metabolic dysfunctions of HCC detected via metabolomics and lipidomics would contribute to a better understanding of clinical relevance of hepatic metabolic reprogramming and provide potential sources for the identification of therapeutic targets and the discovery of biomarkers.

SUBMITTER: Wang Q

PROVIDER: S-EPMC8997969 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Metabolic Reprogramming and Its Relationship to Survival in Hepatocellular Carcinoma.

Wang Qingqing Q Tan Yexiong Y Jiang Tianyi T Wang Xiaolin X Li Qi Q Li Yanli Y Dong Liwei L Liu Xinyu X Xu Guowang G

Cells 20220322 7

Hepatocarcinogenesis is frequently accompanied by substantial metabolic reprogramming to maximize the growth and proliferation of cancer cells. In this study, we carried out a comprehensive study of metabolomics and lipidomics profiles combined with gene expression analysis to characterize the metabolic reprogramming in hepatocellular carcinoma (HCC). Compared with adjacent noncancerous liver tissue, the enhanced aerobic glycolysis and de novo lipogenesis (DNL) and the repressed urea cycle were ...[more]

PMID: 35406630

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Project description:Background & aimsThe mechanism behind the progressive pathological alteration in metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH)-associated hepatocellular carcinoma (HCC) is poorly understood. In the present study, we investigated the role of the polyol pathway enzyme AKR1B1 in metabolic switching associated with MASLD/MASH and in the progression of HCC.MethodsAKR1B1 expression was estimated in the tissue and plasma of patients with MASLD/MASH, HCC, and HCC with diabetes mellitus. The role of AKR1B1 in metabolic switching in vitro was assessed through media conditioning, lentiviral transfection, and pharmacological probes. A proteomic and metabolomic approach was applied for the in-depth investigation of metabolic pathways. Preclinically, mice were subjected to a high-fructose diet and diethylnitrosamine to investigate the role of AKR1B1 in the hyperglycemia-mediated metabolic switching characteristic of MASLD-HCC.ResultsA significant increase in the expression of AKR1B1 was observed in tissue and plasma samples from patients with MASLD/MASH, HCC, and HCC with diabetes mellitus compared to normal samples. Mechanistically, in vitro assays revealed that AKR1B1 modulates the Warburg effect, mitochondrial dynamics, the tricarboxylic acid cycle, and lipogenesis to promote hyperglycemia-mediated MASLD and cancer progression. A pathological increase in the expression of AKR1B1 was observed in experimental MASLD-HCC, and expression was positively correlated with high blood glucose levels. High-fructose diet + diethylnitrosamine-treated animals also exhibited statistically significant elevation of metabolic markers and carcinogenesis markers. AKR1B1 inhibition with epalrestat or NARI-29 inhibited cellular metabolism in in vitro and in vivo models.ConclusionsPathological AKR1B1 modulates hepatic metabolism to promote MASLD-associated hepatocarcinogenesis. Aldose reductase inhibition modulates the glycolytic pathway to prevent precancerous hepatocyte formation.Impact and implicationsThis research work highlights AKR1B1 as a druggable target in metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC), which could provide the basis for the development of new chemotherapeutic agents. Moreover, our results indicate the potential of plasma AKR1B1 levels as a prognostic marker and diagnostic test for MASLD and associated HCC. Additionally, a major observation in this study was that AKR1B1 is associated with the promotion of the Warburg effect in HCC.

Dataset Information

Metabolic Reprogramming and Its Relationship to Survival in Hepatocellular Carcinoma.

Publications

Metabolic Reprogramming and Its Relationship to Survival in Hepatocellular Carcinoma.

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