Abstract
Uric acid (UA) is the end product of the catabolism of purines, and its serum levels are commonly increased in cancer patients. We aimed to explore the transcriptional regulation of tumour uricogenesis in human tumours, and relate uricogenesis with tumour pathological and pharmacological findings. Using data from The Cancer Genome Atlas (TCGA), we analysed the expression levels of xanthine dehydrogenase (XDH) and adenine phosphoribosyltransferase (APRT), two key enzymes in UA production and the purine salvage pathway, respectively. We found large differences between tumour types and individual tumours in their expression of XDH and APRT. Variations in locus-specific DNA methylation and gene copy number correlated with the expression levels of XDH and APRT in human tumours respectively. We explored the consequences of this differential regulation of uricogenesis. Tumours with high levels of XDH mRNA were characterised by higher expression of several genes encoding pro-inflammatory and immune cytokines, and increased levels of tumour infiltration with immune cells. Finally, we studied cancer drug sensitivity using data from the National Cancer Institute-60 (NCI-60) database. A specific correlation was found between the expression levels of APRT and cell sensitivity to the chemotherapeutic agent 5-fluorouracil (5-FU). Our findings underline the existence of great differences in uricogenesis between different types of human tumours. The study of uricogenesis offers promising perspectives for the identification of clinically relevant molecular biomarkers and for tumour stratification in the therapeutic context.
Highlights
Uric acid (UA) is the end product of the catabolism of purines
To address the tumour-intrinsic regulation of uricogenesis, we examined the expression of the three genes encoding the core enzymes of uricogenesis, i.e. adenine phosphoribosyltransferase (APRT), HPRT1 and xanthine dehydrogenase/xanthine oxidase (XDH) (Figure 1)
We found a striking heterogeneity in the expression of these genes: median expression of the gene XDH showed the most striking heterogeneity with some tumours expressing negligible levels of XDH while others were characterised by high XDH expression levels (PAAD, hepatocellular carcinoma (HCC) and head and neck squamous cell carcinoma (HNSCC))
Summary
Uric acid (UA) is the end product of the catabolism of purines It is well-known for its ability to precipitate and form crystals, characteristic of gout, a sterile inflammatory syndrome of the joints [1,2,3]. The rate of UA synthesis is limited by the existence of a purine salvage pathway, catalysed by the enzymes hypoxanthine phosphoribosyltransferase (HPRT, gene HPRT1) and adenine phosphoribosyltransferase c 2018 The Author(s).
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