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Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis

Journal article
Authors R. Benfeitas
G. Bidkhori
B. Mukhopadhyay
Martina Klevstig
M. Arif
C. Zhang
S. Lee
R. Cinar
J. Nielsen
M. Uhlen
Jan Borén
G. Kunos
A. Mardinoglu
Published in Ebiomedicine
Volume 40
Pages 471-487
ISSN 2352-3964
Publication year 2019
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 471-487
Language en
Links dx.doi.org/10.1016/j.ebiom.2018.12....
Keywords Hepatocellular carcinoma, Redox metabolism, Systems biology, Precision medicine, Cancer, gene-expression, oxidative stress, class discovery, poor-prognosis, genome-scale, cancer, survival, progression, metabolism, prediction, General & Internal Medicine, Research & Experimental Medicine
Subject categories Cancer and Oncology

Abstract

Background: Redox metabolism is often considered a potential target for cancer treatment, but a systematic examination of redox responses in hepatocellular carcinoma (HCC) is missing. Methods: Here, we employed systems biology and biological network analyses to reveal key roles of genes associated with redox metabolism in HCC by integrating multi-omics data. Findings: We found that several redox genes, including 25 novel potential prognostic genes, are significantly co-expressed with liver-specific genes and genes associated with immunity and inflammation. Based on an integrative analysis, we found that HCC tumors display antagonistic behaviors in redox responses. The two HCC groups are associated with altered fatty acid, amino acid, drug and hormone metabolism, differentiation, proliferation, and NADPH-independent vs - dependent antioxidant defenses. Redox behavior varies with known tumor subtypes and progression, affecting patient survival. These antagonistic responses are also displayed at the protein and metabolite level and were validated in several independent cohorts. We finally showed the differential redox behavior using mice transcriptomics in HCC and noncancerous tissues and associated with hypoxic features of the two redox gene groups. Interpretation: Our integrative approaches highlighted mechanistic differences among tumors and allowed the identification of a survival signature and several potential therapeutic targets for the treatment of HCC.

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