Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisResearch in context
Rui Benfeitas,
Gholamreza Bidkhori,
Bani Mukhopadhyay,
Martina Klevstig,
Muhammad Arif,
Cheng Zhang,
Sunjae Lee,
Resat Cinar,
Jens Nielsen,
Mathias Uhlen,
Jan Boren,
George Kunos,
Adil Mardinoglu
Affiliations
Rui Benfeitas
Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, Sweden
Gholamreza Bidkhori
Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, Sweden
Bani Mukhopadhyay
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
Martina Klevstig
Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
Muhammad Arif
Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, Sweden
Cheng Zhang
Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, Sweden
Sunjae Lee
Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, Sweden
Resat Cinar
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
Jens Nielsen
Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
Mathias Uhlen
Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, Sweden
Jan Boren
Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
George Kunos
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
Adil Mardinoglu
Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, Sweden; Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden; Centre for Host–Microbiome Interactions, Dental Institute, King's College London, London, UK; Corresponding author.
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. Keywords: Hepatocellular carcinoma, Redox metabolism, Systems biology, Precision medicine, Cancer, Transcriptomics, Liver cancer
