Dataset Information

Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism.

ABSTRACT: Transforming Growth Factor beta (TGF-β) induces tumor cell migration and invasion. However, its role in inducing metabolic reprogramming is poorly understood. Here we analyzed the metabolic profile of hepatocellular carcinoma (HCC) cells that show differences in TGF-β expression. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), metabolomics and transcriptomics were performed. Results indicated that the switch from an epithelial to a mesenchymal/migratory phenotype in HCC cells is characterized by reduced mitochondrial respiration, without significant differences in glycolytic activity. Concomitantly, enhanced glutamine anaplerosis and biosynthetic use of TCA metabolites were proved through analysis of metabolite levels, as well as metabolic fluxes from U-13C6-Glucose and U-13C5-Glutamine. This correlated with increase in glutaminase 1 (GLS1) expression, whose inhibition reduced cell migration. Experiments where TGF-β function was activated with extracellular TGF-β1 or inhibited through TGF-β receptor I silencing showed that TGF-β induces a switch from oxidative metabolism, coincident with a decrease in OCR and the upregulation of glutamine transporter Solute Carrier Family 7 Member 5 (SLC7A5) and GLS1. TGF-β also regulated the expression of key genes involved in the flux of glycolytic intermediates and fatty acid metabolism. Together, these results indicate that autocrine activation of the TGF-β pathway regulates oxidative metabolism in HCC cells.

SUBMITTER: Soukupova J

PROVIDER: S-EPMC5624948 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism.

Soukupova Jitka J Malfettone Andrea A Hyroššová Petra P Hernández-Alvarez María-Isabel MI Peñuelas-Haro Irene I Bertran Esther E Junza Alexandra A Capellades Jordi J Giannelli Gianluigi G Yanes Oscar O Zorzano Antonio A Perales José Carlos JC Fabregat Isabel I

Scientific reports 20171002 1

Transforming Growth Factor beta (TGF-β) induces tumor cell migration and invasion. However, its role in inducing metabolic reprogramming is poorly understood. Here we analyzed the metabolic profile of hepatocellular carcinoma (HCC) cells that show differences in TGF-β expression. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), metabolomics and transcriptomics were performed. Results indicated that the switch from an epithelial to a mesenchymal/migratory phenotype in HCC c ...[more]

PMID: 28970582

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Project description:Background and purposeHypertension is the major risk factor for stroke. Recent work unveiled that hypertension is associated with chronic neuroinflammation; microglia are the major players in neuroinflammation, and the activated microglia elevate sympathetic nerve activity and blood pressure. This study is to understand how brain homeostasis is kept from hypertensive disturbance and microglial activation at the onset of hypertension.MethodsHypertension was induced by subcutaneous delivery of angiotensin II, and blood pressure was monitored in conscious animals. Microglial activity was analyzed by flow cytometry and immunohistochemistry. Antibody, pharmacological chemical, and recombinant cytokine were administered to the brain through intracerebroventricular infusion. Microglial depletion was performed by intracerebroventricular delivering diphtheria toxin to CD11b-diphtheria toxin receptor mice. Gene expression profile in sympathetic controlling nucleus was analyzed by customized qRT-PCR array.ResultsTransforming growth factor-β (TGF-β) is constitutively expressed in the brains of normotensive mice. Removal of TGF-β or blocking its signaling before hypertension induction accelerated hypertension progression, whereas supplementation of TGF-β1 substantially suppressed neuroinflammation, kidney norepinephrine level, and blood pressure. By means of microglial depletion and adoptive transfer, we showed that the effects of TGF-β on hypertension are mediated through microglia. In contrast to the activated microglia in established hypertension, the resting microglia are immunosuppressive and important in maintaining neural homeostasis at the onset of hypertension. Further, we profiled the signature molecules of neuroinflammation and neuroplasticity associated with hypertension and TGF-β by qRT-PCR array.ConclusionsOur results identify that TGF-β-modulated microglia are critical to keeping brain homeostasis responding to hypertensive disturbance.

Dataset Information

Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism.

Publications

Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism.

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