Oncotarget

Research Papers:

Metabolite profiling identifies a signature of tumorigenicity in hepatocellular carcinoma

Shamir Cassim, Valérie-Ann Raymond, Benoit Lacoste, Pascal Lapierre and Marc Bilodeau _

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Oncotarget. 2018; 9:26868-26883. https://doi.org/10.18632/oncotarget.25525

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Abstract

Shamir Cassim1, Valérie-Ann Raymond1, Benoit Lacoste1, Pascal Lapierre1,2 and Marc Bilodeau1,2

1Laboratoire d’hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada

2Département de médecine, Université de Montréal, Montréal, QC, Canada

Correspondence to:

Marc Bilodeau, email: [email protected]

Keywords: liver; hepatocellular carcinoma; glucose; tumorigenicity; metabolic signature

Received: March 26, 2018     Accepted: May 17, 2018     Published: June 01, 2018

ABSTRACT

HCC (Hepatocellular carcinoma) cells exhibit greater metabolic plasticity than normal hepatocytes since they must survive in a dynamic microenvironment where nutrients and oxygen are often scarce. Using a metabolomic approach combined with functional in vitro and in vivo assays, we aimed to identify an HCC metabolic signature associated with increased tumorigenicity and patient mortality. Metabolite profiling of HCC Dt81Hepa1-6 cells revealed that their increased tumorigenicity was associated with elevated levels of glycolytic metabolites. Tumorigenic Dt81Hepa1-6 also had an increased ability to uptake glucose leading to a higher glycolytic flux that stemmed from an increased expression of glucose transporter GLUT-1. Dt81Hepa1-6-derived tumors displayed increased mRNA expressions of glycolytic genes, Hypoxia-inducible factor-1alpha and of Cyclin D1. HCC tumors also displayed increased energy charge, reduced antioxidative metabolites and similar fatty acid biosynthesis compared to healthy liver. Increased tumoral expression of glycolytic and hypoxia signaling pathway mRNAs was associated with decreased survival in HCC patients. In conclusion, HCC cells can rapidly alter their metabolism according to their environment and switch to the use of glucose through aerobic glycolysis to sustain their tumorigenicity and proliferative ability. Therefore, cancer metabolic reprogramming could be essential for the tumorigenicity of HCC cells during cancer initiation and invasion.


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