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Abstract
Heat shock proteins (HSPs) are a large family of ubiquitously expressed proteins with diverse functions, including protein assembly and folding/unfolding. These proteins have been associated with the progression of various gastrointestinal tumours. Dysregulation of cellular redox has also been associated with gastrointestinal carcinogenesis, however, a link between HSPs and dysregulation of cellular redox in carcinogenesis remains unclear. In this study, we analysed mRNA co-expression and methylation patterns, as well as performed survival analysis and gene set enrichment analysis, on gastrointestinal cancer data sets (oesophageal, stomach and colorectal carcinomas) to determine whether HSP activity and cellular redox dysregulation are linked. A widespread relationship between HSPs and cellular redox was identified, with specific combinatorial co-expression patterns demonstrated to significantly alter patient survival outcomes. This comprehensive analysis provides the foundation for future studies aimed at deciphering the mechanisms of cooperativity between HSPs and redox regulatory enzymes, which may be a target for future therapeutic intervention for gastrointestinal tumours.
Highlights
Heat shock proteins (HSPs) are a highly conserved, ubiquitously expressed family of proteins, that act as molecular chaperones to correctly fold a new polypeptide chain, or support the refolding of damaged proteins [1]
Other strong positive correlations in gene expression were identified between superoxide dismutase 1 (SOD1) with CCT8 and glutathione peroxidase 8 (GPX8) with HSPB2
We analysed publicly available The Cancer Genome Atlas (TCGA) datasets from three gastrointestinal tumours utilising a list of 96 HSP family genes and 30 genes that have been implicated in cellular redox functions
Summary
Heat shock proteins (HSPs) are a highly conserved, ubiquitously expressed family of proteins, that act as molecular chaperones to correctly fold a new polypeptide chain, or support the refolding of damaged proteins [1]. Experimental evidence indicates that stress-induced activation of HSPs endows cells with a survival advantage by mechanism(s) that, on the one hand, activate pro-survival networks, and on the other, inhibit apoptotic execution [3]. These attributes and the association with pro-inflammatory signalling lend credence to the involvement of HSPs in promoting carcinogenesis and its progression [4,5]. The differential expression of various HSP family members and dysregulation of redox homeostasis have been individually implicated in tumorigenesis, involving the gastrointestinal (GI) tract [6,7]. The interplay between HSPs and redox regulation in the setting of GI cancers is less widely understood
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