Thyroid hormone inhibits hepatocellular carcinoma progression via induction of differentiation and metabolic reprogramming

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

Download Full-text

Two Metabolomics Phenotypes of Human Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease According to Fibrosis Severity

Metabolites ◽

10.3390/metabo11010054 ◽

2021 ◽

Vol 11 (1) ◽

pp. 54

Author(s):

Benjamin Buchard ◽

Camille Teilhet ◽

Natali Abeywickrama Samarakoon ◽

Sylvie Massoulier ◽

Juliette Joubert-Zakeyh ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Monounsaturated Fatty Acids ◽

Metabolic Reprogramming ◽

Resonance Spectroscopy ◽

Alcoholic Fatty Liver ◽

The Impact ◽

Alcoholic Fatty Liver Disease

Non-Alcoholic Fatty Liver Disease (NAFLD) is considered as the forthcoming predominant cause for hepatocellular carcinoma (HCC). NAFLD-HCC may rise in non-cirrhotic livers in 40 to 50% of patients. The aim of this study was to identify different metabolic pathways of HCC according to fibrosis level (F0F1 vs. F3F4). A non-targeted metabolomics strategy was applied. We analyzed 52 pairs of human HCC and adjacent non-tumoral tissues which included 26 HCC developed in severe fibrosis or cirrhosis (F3F4) and 26 in no or mild fibrosis (F0F1). Tissue extracts were analyzed using 1H-Nuclear Magnetic Resonance spectroscopy. An optimization evolutionary method based on genetic algorithm was used to identify discriminant metabolites. We identified 34 metabolites differentiating the two groups of NAFLD-HCC according to fibrosis level, allowing us to propose two metabolomics phenotypes of NAFLD-HCC. We showed that HCC-F0F1 mainly overexpressed choline derivatives and glutamine, whereas HCC-F3F4 were characterized by a decreased content of monounsaturated fatty acids (FA), an increase of saturated FA and an accumulation of branched amino acids. Comparing HCC-F0F1 and HCC-F3F4, differential expression levels of glucose, choline derivatives and phosphoethanolamine, monounsaturated FA, triacylglycerides were identified as specific signatures. Our metabolomics analysis of HCC tissues revealed for the first time two phenotypes of HCC developed in NAFLD according to fibrosis level. This study highlighted the impact of the underlying liver disease on metabolic reprogramming of the tumor.

Download Full-text

Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms22115543 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5543

Author(s):

Jitka Soukupova ◽

Andrea Malfettone ◽

Esther Bertran ◽

María Isabel Hernández-Alvarez ◽

Irene Peñuelas-Haro ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Lipid Metabolism ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Aerobic Glycolysis ◽

Metabolic Reprogramming ◽

Migration And Invasion ◽

Metabolic Switch ◽

Mesenchymal Transition ◽

Hcc Cells

(1) Background: The transforming growth factor (TGF)-β plays a dual role in liver carcinogenesis. At early stages, it inhibits cell growth and induces apoptosis. However, TGF-β expression is high in advanced stages of hepatocellular carcinoma (HCC) and cells become resistant to TGF-β induced suppressor effects, responding to this cytokine undergoing epithelial–mesenchymal transition (EMT), which contributes to cell migration and invasion. Metabolic reprogramming has been established as a key hallmark of cancer. However, to consider metabolism as a therapeutic target in HCC, it is necessary to obtain a better understanding of how reprogramming occurs, which are the factors that regulate it, and how to identify the situation in a patient. Accordingly, in this work we aimed to analyze whether a process of full EMT induced by TGF-β in HCC cells induces metabolic reprogramming. (2) Methods: In vitro analysis in HCC cell lines, metabolomics and transcriptomics. (3) Results: Our findings indicate a differential metabolic switch in response to TGF-β when the HCC cells undergo a full EMT, which would favor lipolysis, increased transport and utilization of free fatty acids (FFA), decreased aerobic glycolysis and an increase in mitochondrial oxidative metabolism. (4) Conclusions: EMT induced by TGF-β in HCC cells reprograms lipid metabolism to facilitate the utilization of FFA and the entry of acetyl-CoA into the TCA cycle, to sustain the elevated requirements of energy linked to this process.

Download Full-text

Increased invasive activity of human hepatocellular carcinoma cells is associated with an overexpression of thyroid hormone Î²1 nuclear receptor and low expression of the anti-metastatic nm23 gene

Cancer Letters ◽

10.1016/0304-3835(95)04000-t ◽

1995 ◽

Vol 98 (1-2) ◽

pp. 89-95 ◽

Cited By ~ 1

Author(s):

L Kwang-huei

Keyword(s):

Hepatocellular Carcinoma ◽

Thyroid Hormone ◽

Nuclear Receptor ◽

Carcinoma Cells ◽

Human Hepatocellular Carcinoma ◽

Hepatocellular Carcinoma Cells ◽

Nm23 Gene ◽

Human Hepatocellular Carcinoma Cells ◽

Low Expression

Download Full-text

Lipid Metabolic Reprogramming in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers10110447 ◽

2018 ◽

Vol 10 (11) ◽

pp. 447 ◽

Cited By ~ 35

Author(s):

Hayato Nakagawa ◽

Yuki Hayata ◽

Satoshi Kawamura ◽

Tomoharu Yamada ◽

Naoto Fujiwara ◽

...

Keyword(s):

Risk Factors ◽

Hepatocellular Carcinoma ◽

Local Environment ◽

Metabolic Reprogramming ◽

Glutamine Metabolism ◽

Metabolic Alterations ◽

Rich Condition ◽

Visceral Adipose ◽

Hcc Cells

Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies have uncovered the importance of lipid metabolic reprogramming in carcinogenesis. Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC), and individuals with these conditions exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This “lipid-rich condition” is highly characteristic of obesity- and NASH-driven HCC. Although the way in which HCC cells adapt to such a condition and exploit it to aid their progression is not understood, we recently obtained new insights into this mechanism through lipid metabolic reprogramming. In addition, accumulating evidence supports the importance of lipid metabolic reprogramming in various situations of hepatocarcinogenesis. Thus, in this review, we discuss the latest findings regarding the role of FA metabolism pathways in hepatocarcinogenesis, focusing on obesity- and NASH-driven lipid metabolic reprogramming.

Download Full-text

Modularity of the metabolic gene network as a prognostic biomarker for hepatocellular carcinoma

10.1101/224998 ◽

2017 ◽

Author(s):

Fengdan Ye ◽

Dongya Jia ◽

Mingyang Lu ◽

Herbert Levine ◽

Michael W Deem

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Biomarker ◽

Malignant Tumors ◽

Aerobic Glycolysis ◽

Expression Patterns ◽

Cancer Recurrence ◽

Metabolic Reprogramming ◽

The Cancer Genome Atlas ◽

Driver Genes ◽

Tumor Stages

AbstractAbnormal metabolism is an emerging hallmark of cancer. Cancer cells utilize both aerobic glycolysis and oxidative phosphorylation (OXPHOS) for energy production and biomass synthesis. Understanding the metabolic reprogramming in cancer can help design therapies to target metabolism and thereby to improve prognosis. We have previously argued that more malignant tumors are usually characterized by a more modular expression pattern of cancer-associated genes. In this work, we analyzed the expression patterns of metabolism genes in terms of modularity for 371 hepatocellular carcinoma (HCC) samples from the Cancer Genome Atlas (TCGA). We found that higher modularity significantly correlated with glycolytic phenotype, later tumor stages, higher metastatic potential, and cancer recurrence, all of which contributed to poorer prognosis. Among patients with recurred tumor, we found the correlation of higher modularity with worse prognosis during early to mid-progression. Furthermore, we developed metrics to calculate individual modularity, which was shown to be predictive of cancer recurrence and patients’ survival and therefore may serve as a prognostic biomarker. Our overall conclusion is that more aggressive HCC tumors, as judged by decreased host survival probability, had more modular expression patterns of metabolic genes. These results may be used to identify cancer driver genes and for drug design.

Download Full-text

Eight-Gene Metabolic Signature Related with Tumor-Associated Macrophages Predicting Overall Survival for Hepatocellular Carcinoma

10.21203/rs.3.rs-36554/v1 ◽

2020 ◽

Author(s):

Junyu Huo ◽

Yunjin Zang ◽

Hongjing Dong ◽

Xiaoqiang Liu ◽

Fu He ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Survival Analysis ◽

Risk Score ◽

Risk Group ◽

Cancer Genome ◽

Metabolic Reprogramming ◽

Tumor Associated Macrophages ◽

Kaplan Meier ◽

The Relationship

Abstract Background: In recent years, the relationship between tumor associated macrophages (TAMs) and solid tumors has become a research hotspot. The study aims at exploring the close relationship of TAMs with metabolic reprogramming genes in hepatocellular carcinoma(HCC), in order to provide a new way of treatment for HCC.Materials and methods: The study selected 343 HCC patients with complete survival information(survival time >= 1month) in the Cancer Genome Atlas (TCGA) as the study objects. Kaplan-Meier survival analysis assisted in figuring out the relationship between macrophage infiltration level and overall survival (OS), and Pearson correlation test to identify metabolic reprogramming genes(MRGs) related to tumor macrophage abundance. Lasso regression algorithm were conducted on prognosis related MRGs screened by Univariate Cox regression analysis and Kaplan-Meier survival analysis to construct the riskscore, another independent cohort (including 228 HCC patients) from the International Cancer Genome Consortium (ICGC) were used for external validation regarding the prognostic signature.Results: A risk score composed of 8 metabolic genes can accurately predict the OS of training cohort(TCGA) and testing cohort(ICGC). It is important that the risk score could widely used for people with different clinical characteristics, and is an independent predictor independent of other clinical factors affecting prognosis. As expected, high-risk group exhibited an obviously higher macrophage abundance relative to low-risk group, and the risk score presented a positive relation to the expression level of three commonly used immune checkpoints(PD1,PDL1,CTLA4).Conclusion: Our study constructed and validated a novel eight‑gene signature for predicting HCC patients’ OS, which possibly contributed to making clinical treatment decisions.

Download Full-text

Construction and Validation of a Metabolic Reprogramming Related Prognostic Model for Hepatocellular Carcinoma

10.21203/rs.3.rs-97188/v1 ◽

2020 ◽

Author(s):

Xiaohong - Liu ◽

Qian - Xu ◽

Zi-Jing - Li ◽

Bin - Xiong

Keyword(s):

Hepatocellular Carcinoma ◽

Regression Analysis ◽

Risk Score ◽

Prognostic Model ◽

Cox Regression ◽

Expression Profiles ◽

Prognostic Significance ◽

Metabolic Reprogramming ◽

Cox Regression Analysis ◽

Metabolic Genes

Abstract BackgroundMetabolic reprogramming is an important hallmark in the development of malignancies. Numerous metabolic genes have been demonstrated to participate in the progression of hepatocellular carcinoma (HCC). However, the prognostic significance of the metabolic genes in HCC remains elusive. MethodsWe downloaded the gene expression profiles and clinical information from the GEO, TCGA and ICGC databases. The differently expressed metabolic genes were identified by using Limma R package. Univariate Cox regression analysis and LASSO (Least absolute shrinkage and selection operator) Cox regression analysis were utilized to uncover the prognostic significance of metabolic genes. A metabolism-related prognostic model was constructed in TCGA cohort and validated in ICGC cohort. Furthermore, we constructed a nomogram to improve the accuracy of the prognostic model by using the multivariate Cox regression analysis.ResultsThe high-risk score predicted poor prognosis for HCC patients in the TCGA cohort, as confirmed in the ICGC cohort (P < 0.001). And in the multivariate Cox regression analysis, we observed that risk score could act as an independent prognostic factor for the TCGA cohort (HR (hazard ratio) 3.635, 95% CI (confidence interval)2.382-5.549) and the ICGC cohort (HR1.905, 95%CI 1.328-2.731). In addition, we constructed a nomogram for clinical use, which suggested a better prognostic model than risk score.ConclusionsOur study identified several metabolic genes with important prognostic value for HCC. These metabolic genes can influence the progression of HCC by regulating tumor biology and can also provide metabolic targets for the precise treatment of HCC.

Download Full-text

Mito-Nuclear Communication in Hepatocellular Carcinoma Metabolic Rewiring

Cells ◽

10.3390/cells8050417 ◽

2019 ◽

Vol 8 (5) ◽

pp. 417 ◽

Cited By ~ 8

Author(s):

Tommaso Mello ◽

Irene Simeone ◽

Andrea Galli

Keyword(s):

Hepatocellular Carcinoma ◽

Driving Force ◽

Cancer Biology ◽

Metabolic Disorders ◽

Prolonged Exposure ◽

Neoplastic Transformation ◽

Metabolic Reprogramming ◽

Whole Body ◽

Energy Requirements ◽

Acquired Drug Resistance

As the main metabolic and detoxification organ, the liver constantly adapts its activity to fulfill the energy requirements of the whole body. Despite the remarkable adaptive capacity of the liver, prolonged exposure to noxious stimuli such as alcohol, viruses and metabolic disorders results in the development of chronic liver disease that can progress to hepatocellular carcinoma (HCC), which is currently the second leading cause of cancer-related death worldwide. Metabolic rewiring is a common feature of cancers, including HCC. Altered mito-nuclear communication is emerging as a driving force in the metabolic reprogramming of cancer cells, affecting all aspects of cancer biology from neoplastic transformation to acquired drug resistance. Here, we explore relevant aspects (and discuss recent findings) of mito-nuclear crosstalk in the metabolic reprogramming of hepatocellular carcinoma.

Download Full-text