Dataset Information

Metabolite profiling identifies a signature of tumorigenicity in hepatocellular carcinoma.

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.

SUBMITTER: Cassim S

PROVIDER: S-EPMC6003570 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Metabolite profiling identifies a signature of tumorigenicity in hepatocellular carcinoma.

Cassim Shamir S Raymond Valérie-Ann VA Lacoste Benoit B Lapierre Pascal P Bilodeau Marc M

Oncotarget 20180601 42

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 <i>in vitro</i> and <i>in vivo</i> 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 ...[more]

PMID: 29928490

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Project description:Alternative splicing (AS) is a pervasive and vital mechanism involved in the progression of cancer by expanding genomic encoding capacity and increasing protein complexity. However, the systematic analysis of AS in hepatocellular carcinoma (HCC) is lacking and urgently required. In the present study, genome?wide AS events with corresponding clinical information were profiled in 290 patients with HCC from the Cancer Genome Atlas and SpliceSeq software. Functional enrichment analyses revealed the pivotal biological process of AS regulation. Univariate Cox regression analyses were performed, followed by stepwise forward multivariate analysis to develop the prognostic signatures. Spearman's correlation analyses were also used to construct potential regulatory network between the AS events and aberrant splicing factors. A total of 34,163 AS events were detected, among which 1,805 AS events from 1,314 parent genes were significantly associated with the overall survival (OS) of patients with HCC, and their parent genes serve crucial roles in HCC?related oncogenic processes, including the p53 signaling pathway, AMPK signaling pathway and HIF?1 signaling pathway. A prognostic AS signature was established that was found to be an independent prognostic factor for OS in stratified cohorts, harboring a noteworthy ability to distinguish between the distinct prognoses of patients with HCC (high?risk vs. low?risk, 827 vs. 3,125 days, P<2e?16). Time?dependent receiver?-operator characteristic curves confirmed its robustness and clinical efficacy, with the area under the curves maintained >0.9 for short?term and long?term prognosis prediction. The splicing correlation network suggested a trend in the interactions between splicing factors and prognostic AS events, further revealing the underlying mechanism of AS in the oncogenesis of HCC. In conclusion, the present study provides a comprehensive portrait of global splicing alterations involved in the progression and HCC in addition to valuable prognostic factors for patients, which may represent as underappreciated hallmark and provide novel clues of therapeutic targets in HCC.

Dataset Information

Metabolite profiling identifies a signature of tumorigenicity in hepatocellular carcinoma.

Publications

Metabolite profiling identifies a signature of tumorigenicity in hepatocellular carcinoma.

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