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

(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 suppres...

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Autores principales: Soukupova, Jitka, Malfettone, Andrea, Bertran, Esther, Hernández-Alvarez, María Isabel, Peñuelas-Haro, Irene, Dituri, Francesco, Giannelli, Gianluigi, Zorzano, Antonio, Fabregat, Isabel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197297/
https://www.ncbi.nlm.nih.gov/pubmed/34073989
http://dx.doi.org/10.3390/ijms22115543
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author Soukupova, Jitka
Malfettone, Andrea
Bertran, Esther
Hernández-Alvarez, María Isabel
Peñuelas-Haro, Irene
Dituri, Francesco
Giannelli, Gianluigi
Zorzano, Antonio
Fabregat, Isabel
author_facet Soukupova, Jitka
Malfettone, Andrea
Bertran, Esther
Hernández-Alvarez, María Isabel
Peñuelas-Haro, Irene
Dituri, Francesco
Giannelli, Gianluigi
Zorzano, Antonio
Fabregat, Isabel
author_sort Soukupova, Jitka
collection PubMed
description (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.
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spelling pubmed-81972972021-06-13 Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism Soukupova, Jitka Malfettone, Andrea Bertran, Esther Hernández-Alvarez, María Isabel Peñuelas-Haro, Irene Dituri, Francesco Giannelli, Gianluigi Zorzano, Antonio Fabregat, Isabel Int J Mol Sci Article (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. MDPI 2021-05-24 /pmc/articles/PMC8197297/ /pubmed/34073989 http://dx.doi.org/10.3390/ijms22115543 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Soukupova, Jitka
Malfettone, Andrea
Bertran, Esther
Hernández-Alvarez, María Isabel
Peñuelas-Haro, Irene
Dituri, Francesco
Giannelli, Gianluigi
Zorzano, Antonio
Fabregat, Isabel
Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism
title Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism
title_full Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism
title_fullStr Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism
title_full_unstemmed Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism
title_short Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism
title_sort epithelial–mesenchymal transition (emt) induced by tgf-β in hepatocellular carcinoma cells reprograms lipid metabolism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197297/
https://www.ncbi.nlm.nih.gov/pubmed/34073989
http://dx.doi.org/10.3390/ijms22115543
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