Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment

Berndt, Nikolaus; Eckstein, Johannes; Heucke, Niklas; Wuensch, Tilo; Gajowski, Robert; Stockmann, Martin; Meierhofer, David; Holzhütter, Hermann−Georg

doi:10.1111/febs.15587

Cited by 13 publications

(12 citation statements)

References 53 publications

(66 reference statements)

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“…From a purely functional point of view, however, the lipid content was clearly increased in PHCs. Our data are in line with results showing high free fatty acid uptake and ß-oxidation rates in HCC, indicating high lipid metabolism [ 54 ].…”

Section: Discussionsupporting

confidence: 92%

Critical Investigation of the Usability of Hepatoma Cell Lines HepG2 and Huh7 as Models for the Metabolic Representation of Resectable Hepatocellular Carcinoma

Schicht

Seidemann

Hänsel

et al. 2022

Cancers

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Metabolic alterations in hepatocellular carcinoma (HCC) are fundamental for the development of diagnostic screening and therapeutic intervention since energy metabolism plays a central role in differentiated hepatocytes. In HCC research, hepatoma cell lines (HCLs) like HepG2 and Huh7 cells are still the gold standard. In this study, we characterized the metabolic profiles of primary human hepatoma cells (PHCs), HCLs and primary human hepatocytes (PHHs) to determine their differentiation states. PHCs and PHHs (HCC-PHHs) were isolated from surgical specimens of HCC patients and their energy metabolism was compared to PHHs from non-HCC patients and the HepG2 and Huh7 cells at different levels (transcript, protein, function). Our analyses showed successful isolation of PHCs with a purity of 50–73% (CK18+). The transcript data revealed that changes in mRNA expression levels had already occurred in HCC-PHHs. While many genes were overexpressed in PHCs and HCC-PHHs, the changes were mostly not translated to the protein level. Downregulated metabolic key players of PHCs revealed a correlation with malign transformation and were predominantly pronounced in multilocular HCC. Therefore, HCLs failed to reflect these expression patterns of PHCs at the transcript and protein levels. The metabolic characteristics of PHCs are closer to those of HCC-PHHs than to HCLs. This should be taken into account for future optimized tumor metabolism research.

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Section: Discussionsupporting

confidence: 92%

Critical Investigation of the Usability of Hepatoma Cell Lines HepG2 and Huh7 as Models for the Metabolic Representation of Resectable Hepatocellular Carcinoma

Schicht

Seidemann

Hänsel

et al. 2022

Cancers

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“…Changes in metabolic processes represent key drivers of tumorigenesis and malignancy in the liver 28 . However, whether AUF1 could regulate liver metabolism favoring HCC progression is still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…Changes in metabolic processes represent key drivers of tumorigenesis and malignancy in the liver. 28 However, whether AUF1 could regulate liver metabolism favoring HCC progression is still poorly understood. In this study, we demonstrated that organic hydroxy compound metabolism was the most significantly enriched pathway altered by AUF1 ablation, which enriched 23 AUF1‐dependent genes.…”

Section: Discussionmentioning

confidence: 99%

E2F1‐mediated AUF1 upregulation promotes HCC development and enhances drug resistance via stabilization of AKR1B10

et al. 2022

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The AU-rich binding factor 1 (AUF1) is one of the well known adenylate-uridylate-rich element (ARE)-specific RNA-binding proteins (ARE-BPs) for which dysregulation has been reported in various human cancers. However, the involvement of AUF1 in the initiation and progression of hepatocellular carcinoma (HCC) is still elusive. In this study, we aimed at exploring the clinical significance, function, and mechanism of the abnormal expression of AUF1 in HCC. Using a bioinformatics analysis of The Cancer Genome Atlas (TCGA) and Liver Cancer Institute (LCI) database, we identified that AUF1 was abnormally highly expressed in HCC tissues and that the high expression of AUF1 was correlated with poor prognosis in patients with HCC. We also confirmed the increased AUF1 expression and its prognostic value in our HBV-related HCC cohorts. AUF1 overexpression in hepatoma cells promoted cell proliferation and increased the resistance of hepatoma cells toward doxorubicin, whereas knockdown of AUF1 exerted the opposite effects. Mechanistically, we demonstrated that AKR1B10 was a critical target of AUF1 and was essential for sustaining the AUF1-induced proliferation and drug resistance of hepatoma cells. AUF1 increased AKR1B10 expression by binding to the 3′UTR region of AKR1B10 mRNA and stabilizing AKR1B10 mRNA.Additionally, we demonstrated that E2F1 enhanced AUF1 expression in HCC at the transcription level. Our study revealed a novel role of AUF1 in promoting the development and drug resistance of HCC via the post-transcriptional regulation of AKR1B10 expression. The E2F1/AUF1/AKR1B10 axis can serve as a potential therapeutic target in HCC.

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“…Benefits of a carbohydrate-restricted diet on hepatic steatosis have been studied using a similar multi-omics approach (Mardinoglu et al, 2018 ). A similar workflow is applied for kinetic pathway models, for instance to study metabolic heterogeneity in HCC based on proteomics data (Berndt et al, 2021 ).…”

Section: Clinical and Experimental Partmentioning

confidence: 99%

Hepatectomy-Induced Alterations in Hepatic Perfusion and Function - Toward Multi-Scale Computational Modeling for a Better Prediction of Post-hepatectomy Liver Function

et al. 2021

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Liver resection causes marked perfusion alterations in the liver remnant both on the organ scale (vascular anatomy) and on the microscale (sinusoidal blood flow on tissue level). These changes in perfusion affect hepatic functions via direct alterations in blood supply and drainage, followed by indirect changes of biomechanical tissue properties and cellular function. Changes in blood flow impose compression, tension and shear forces on the liver tissue. These forces are perceived by mechanosensors on parenchymal and non-parenchymal cells of the liver and regulate cell-cell and cell-matrix interactions as well as cellular signaling and metabolism. These interactions are key players in tissue growth and remodeling, a prerequisite to restore tissue function after PHx. Their dysregulation is associated with metabolic impairment of the liver eventually leading to liver failure, a serious post-hepatectomy complication with high morbidity and mortality. Though certain links are known, the overall functional change after liver surgery is not understood due to complex feedback loops, non-linearities, spatial heterogeneities and different time-scales of events. Computational modeling is a unique approach to gain a better understanding of complex biomedical systems. This approach allows (i) integration of heterogeneous data and knowledge on multiple scales into a consistent view of how perfusion is related to hepatic function; (ii) testing and generating hypotheses based on predictive models, which must be validated experimentally and clinically. In the long term, computational modeling will (iii) support surgical planning by predicting surgery-induced perfusion perturbations and their functional (metabolic) consequences; and thereby (iv) allow minimizing surgical risks for the individual patient. Here, we review the alterations of hepatic perfusion, biomechanical properties and function associated with hepatectomy. Specifically, we provide an overview over the clinical problem, preoperative diagnostics, functional imaging approaches, experimental approaches in animal models, mechanoperception in the liver and impact on cellular metabolism, omics approaches with a focus on transcriptomics, data integration and uncertainty analysis, and computational modeling on multiple scales. Finally, we provide a perspective on how multi-scale computational models, which couple perfusion changes to hepatic function, could become part of clinical workflows to predict and optimize patient outcome after complex liver surgery.

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Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment

Abstract: Metabolic characterization of human HCC N. Berndt et al.

Cited by 13 publications

References 53 publications

Critical Investigation of the Usability of Hepatoma Cell Lines HepG2 and Huh7 as Models for the Metabolic Representation of Resectable Hepatocellular Carcinoma

Critical Investigation of the Usability of Hepatoma Cell Lines HepG2 and Huh7 as Models for the Metabolic Representation of Resectable Hepatocellular Carcinoma

E2F1‐mediated AUF1 upregulation promotes HCC development and enhances drug resistance via stabilization of AKR1B10

Hepatectomy-Induced Alterations in Hepatic Perfusion and Function - Toward Multi-Scale Computational Modeling for a Better Prediction of Post-hepatectomy Liver Function

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