Anti-oxidative stress response genes: bioinformatic analysis of their expression and relevance in multiple cancers
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Barak Rotblat1,*, Thomas G. P. Grunewald2,*, Gabriel Leprivier3,*, Gerry Melino1,4, Richard A. Knight1
1 Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK
2 INSERM Unit 830 “Genetics and Biology of Cancer”, Institut Curie Research Center, Paris, France
3 Department of Molecular Oncology, British Columbia Cancer Research Centre and Department of Pathology, University of British Columbia, Vancouver, BC, Canada
4 Department of Experimental Medicine and Surgery, Biochemistry IDI-IRCCS Laboratory, University of Rom ‘Tor Vergata’, Rome, Italy
* Equal contribution authors
Barak Rotblat, email:
Keywords: anti-oxidant genes, glutathione, thioredoxin, breast cancer, lung cancer, NRF2, G6PD
Received: December 5, 2013 Accepted: December 15, 2013 Published: December 15, 2013
Cells mount a transcriptional anti-oxidative stress (AOS) response program to scavenge reactive oxygen species (ROS) that arise from chemical, physical, and metabolic challenges. This protective program has been shown to reduce carcinogenesis triggered by chemical and physical insults. However, it is also hijacked by established cancers to thrive and proliferate within the hostile tumor microenvironment and to gain resistance against chemo- and radiotherapies. Therefore, targeting the AOS response proteins that are exploited by cancer cells is an attractive therapeutic strategy. In order to identify the AOS genes that are suspected to support cancer progression and resistance, we analyzed the expression patterns of 285 genes annotated for being involved in oxidative stress in 994 tumors and 353 normal tissues. Thereby we identified a signature of 116 genes that are highly overexpressed in multiple cancers while being only minimally expressed in normal tissues. To establish which of these genes are more likely to functionally drive cancer resistance and progression, we further identified those whose overexpression correlates with negative patient outcome in breast and lung carcinoma. Gene-set enrichment, gene ontology, network, and pathway analyses revealed that members of the thioredoxin and glutathione pathways are prominent components of this oncogenic signature and that activation of these pathways is common feature of many cancer entities. Interestingly, a large fraction of these AOS genes are downstream targets of the transcription factors NRF2, NF-kappaB, and FOXM1, and rely on NADPH for their enzymatic activities highlighting promising drug targets. We discuss these findings and propose therapeutic strategies that may be applied to overcome cancer resistance.
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