Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisResearch in context

Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisResearch in context

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 w...

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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2019-02-01
Series:EBioMedicine
Online Access:http://www.sciencedirect.com/science/article/pii/S2352396418306352
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spelling doaj-4406d60ca65448679bcdaa61603a93a72020-11-25T01:19:58ZengElsevierEBioMedicine2352-39642019-02-0140471487Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisResearch in contextRui Benfeitas0Gholamreza Bidkhori1Bani Mukhopadhyay2Martina Klevstig3Muhammad Arif4Cheng Zhang5Sunjae Lee6Resat Cinar7Jens Nielsen8Mathias Uhlen9Jan Boren10George Kunos11Adil Mardinoglu12Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, SwedenScience for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, SwedenLaboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USADepartment of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, SwedenScience for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, SwedenScience for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, SwedenScience for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, SwedenLaboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USADepartment of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, SwedenScience for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21 Stockholm, SwedenDepartment of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, SwedenLaboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USAScience 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 cancerhttp://www.sciencedirect.com/science/article/pii/S2352396418306352
collection DOAJ
language English
format Article
sources DOAJ
author 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
spellingShingle 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
Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisResearch in context
EBioMedicine
author_facet 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
author_sort Rui Benfeitas
title Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisResearch in context
title_short Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisResearch in context
title_full Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisResearch in context
title_fullStr Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisResearch in context
title_full_unstemmed Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisResearch in context
title_sort characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysisresearch in context
publisher Elsevier
series EBioMedicine
issn 2352-3964
publishDate 2019-02-01
description 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
url http://www.sciencedirect.com/science/article/pii/S2352396418306352
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