Integrated Metabolite and Gene Expression Profiles Identify Lipid Biomarkers Associated With Progression of Hepatocellular Carcinoma and Patient Outcomes

Abstract

BACKGROUND & AIMS We combined gene expression and metabolic profiling analyses to identify factors associated with outcomes of patients with hepatocellular carcinoma (HCC). METHODS We compared metabolic and gene expression patterns between paired tumor and non-tumor tissues from 30 patients with HCC, and validated the results using samples from 356 patients with HCC. A total of 469 metabolites were measured using liquid chromatography/mass spectrometry and gas chromatography/mass spectrometry. Metabolic and genomic data were integrated, and Kaplan-Meier and Cox proportional hazards analyses were used to associate specific patterns with patient outcomes. Associated factors were evaluated for their effects on cancer cells in vitro and tumor formation in nude mice. RESULTS We identified 28 metabolites and 169 genes associated with aggressive HCC. Lipid metabolites of stearoyl-CoA-desaturase (SCD) activity were associated with aberrant palmitate signaling in aggressive HCC samples. Expression of gene products associated with these metabolites, including SCD, were independently associated with survival times and tumor recurrence in the test and validation sets. Combined expression of SCD and α-fetoprotein were associated with outcomes of patients with early-stage HCC. Levels of MUPA (monounsaturated palmitic acid), the product of SCD activity, were increased in aggressive HCCs; MUPA increased migration and invasion of cultured HCC cells and colony formation by HCC cells. HCC cells that expressed small interfering RNA against SCD had decreased cell migration and colony formation in culture and reduced tumorigenicity in mice. CONCLUSIONS Using a combination of gene expression and metabolotic profile analysis, we identified a lipogenic network that involves SCD and palmitate signaling and was associated with HCC progression and patient outcomes.

CYP3A4 Gene Is a Novel Biomarker for Predicting a Poor Prognosis in Hepatocellular Carcinoma

“…Both RT-PCR and IHC correlated with the findings of the microarray analysis, and we identified CYP3A4 as a novel, potential clinically useful biomarker for the prognosis of HCC. Although many reports have performed comprehensive microarray analyses of the GEP for patients with HCC (10,(17)(18)(19)(20)(21)(22)(23)(24), the frequency of down-regulation and the prognostic impact of the CYP3A4 gene have not yet described in any reports of integrated microarray analyses. Most of these reports have instead focused on genes related to cancer pathways, and few have focused on the frequency of aberrant gene expression and their impact on the prognosis.…”

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Differential lipid metabolism is an important risk factor in liver cancer [99][100][101]. Accordingly, the expression of stearoyl-CoA desaturase, a membrane protein of the endoplasmic reticulum that catalyzes the formation of monounsaturated fatty acids from saturated fatty acids, was found to be associated with aggressiveness of HCC [100][101][102].…”

“…Accordingly, the expression of stearoyl-CoA desaturase, a membrane protein of the endoplasmic reticulum that catalyzes the formation of monounsaturated fatty acids from saturated fatty acids, was found to be associated with aggressiveness of HCC [100][101][102]. Moreover, suppression of stearoyl-CoA desaturase could reduce proliferation in HCC cell lines in an Akt-dependent fashion [100].…”

Lipid Metabolism in Liver Cancer

“…On one hand, the enforced glycolysis over mitochondrial oxygen respiration (also called Warburg effect), although comparatively lower in reaction rates (fourfold increase) than the other types of tumor, was a common metabolic phenotype in tumor. This phonotype was evidenced by the following metabolic changes including the decrease in glucose, citrate, and glycerol 3-phosphate but the increase in lactic acid and pyruvate [64][65][66][67][68][69]. On the other hand, the common induction of beta-oxidation was exemplified by the elevation of 2-oxoglutarate and reduction of free fatty acids, carnitine and carnitine esters [61,64,66,68,[70][71][72][73].…”