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

Abstract

(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.

Quantifying the Patterns of Metabolic Plasticity and Heterogeneity along the Epithelial–Hybrid–Mesenchymal Spectrum in Cancer

“…This overall observation is in accordance with many experimental studies that point towards a negative association between oxidative phosphorylation and the EMT [ 41 , 42 , 43 , 44 ]. However, this relationship is not exclusive, i.e., these quantities could be positively correlated in a variety of contexts, as reported in other experimental studies [ 45 , 46 , 47 ]. Among all pairs of correlations between OXPHOS signature and EMT metrics, the OXPHOS-hallmark EMT pair showed the strongest propensity of negative association with one another, among all pairwise comparisons that showed a significant trend in either direction ( Figure 2 B).…”

Numb-PRRL promotes TGF-β1- and EGF-induced epithelial-to-mesenchymal transition in pancreatic cancer

“…TGF-β1 serves an important role in regulating cell growth, proliferation, differentiation, extracellular matrix synthesis, and the development of EMT [ 28 , 29 ]. TGF-β1-Smad2/3-Snail signaling is the critical molecular pathway involving the development of EMT in several cancers, including lung cancer [ 30 ], breast cancer [ 31 ], liver [ 32 ], and PC [ 5 ]. TGF-β1 activates the receptor complex leads to the activation of Smad2 and Smad3 through direct C-terminal phosphorylation [ 33 ].…”

The Interplay Between TGF-β Signaling and Cell Metabolism

“…Many studies report that TGF-β suppresses the expression of fatty acid synthase during the induction of EMT in cancer cells ( Jiang et al, 2015 ; Yang et al, 2016 ; Liu et al, 2020 ). In Hep3B cells, TGF-β causes a significant reduction in carnitine-conjugated fatty acids, which coincides with upregulation of fatty acid transporter genes, implying increased carnitine-mediated entry of fatty acids into mitochondria that are destined for β-oxidation ( Soukupova et al, 2021 ). In addition, TGF-β2 or TGF-β3, but not TGF-β1, is shown to reinforce fatty acid oxidation in myotubules and adipocytes ( Takahashi et al, 2019 ).…”