Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular Carcinoma

Zeribe Chike Nwosu; Dominik Andre Megger; Seddik Hammad; Barbara Sitek; Stephanie Roessler; Matthias Philip Ebert; Christoph Meyer; Steven Dooley

doi:10.1016/j.jcmgh.2017.05.004

Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular Carcinoma

Cell Mol Gastroenterol Hepatol. 2017 May 31;4(2):303-323.e1. doi: 10.1016/j.jcmgh.2017.05.004. eCollection 2017 Sep.

Authors

Zeribe Chike Nwosu^{1

2}, Dominik Andre Megger^{3

4}, Seddik Hammad^{1

2

5}, Barbara Sitek³, Stephanie Roessler⁶, Matthias Philip Ebert¹, Christoph Meyer^{1

2}, Steven Dooley^{1

2}

Affiliations

¹ Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
² Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
³ Medizinisches Proteom-Center, Department of Clinical Proteomics, Ruhr-Universität Bochum, Bochum, Germany.
⁴ Institute of Virology, University Hospital, University Duisburg-Essen, Essen, Germany.
⁵ Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
⁶ Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Abstract

Background & aims: Cancer cells rely on metabolic alterations to enhance proliferation and survival. Metabolic gene alterations that repeatedly occur in liver cancer are largely unknown. We aimed to identify metabolic genes that are consistently deregulated, and are of potential clinical significance in human hepatocellular carcinoma (HCC).

Methods: We studied the expression of 2,761 metabolic genes in 8 microarray datasets comprising 521 human HCC tissues. Genes exclusively up-regulated or down-regulated in 6 or more datasets were defined as consistently deregulated. The consistent genes that correlated with tumor progression markers (ECM2 and MMP9) (Pearson correlation P < .05) were used for Kaplan-Meier overall survival analysis in a patient cohort. We further compared proteomic expression of metabolic genes in 19 tumors vs adjacent normal liver tissues.

Results: We identified 634 consistent metabolic genes, ∼60% of which are not yet described in HCC. The down-regulated genes (n = 350) are mostly involved in physiologic hepatocyte metabolic functions (eg, xenobiotic, fatty acid, and amino acid metabolism). In contrast, among consistently up-regulated metabolic genes (n = 284) are those involved in glycolysis, pentose phosphate pathway, nucleotide biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, proton transport, membrane lipid, and glycan metabolism. Several metabolic genes (n = 434) correlated with progression markers, and of these, 201 predicted overall survival outcome in the patient cohort analyzed. Over 90% of the metabolic targets significantly altered at the protein level were similarly up- or down-regulated as in genomic profile.

Conclusions: We provide the first exposition of the consistently altered metabolic genes in HCC and show that these genes are potentially relevant targets for onward studies in preclinical and clinical contexts.

Keywords: EMT, epithelial to mesenchymal transition; FA, fatty acid; HCC; HCC, hepatocellular carcinoma; Liver Cancer; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NB, nucleotide biosynthesis; OXPHOS, oxidative phosphorylation; PPP, pentose phosphate pathway; TCA, tricarboxylic acid; TCGA, The Cancer Genome Atlas; Tumor Metabolism; XM, xenobiotics metabolism; logFC, log of fold change.