Equipe CHIMERE, Université de Picardie Jules Verne, Amiens, France.
Laboratoire d'Oncobiologie Moléculaire, Centre de Biologie Humaine, CHU Sud, Amiens, France.
Biosci Rep. 2018 Sep 19;38(5). doi: 10.1042/BSR20171716. Print 2018 Oct 31.
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 and Variations in locus-specific DNA methylation and gene copy number correlated with the expression levels of and in human tumours respectively. We explored the consequences of this differential regulation of uricogenesis. Tumours with high levels of 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 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.
尿酸（UA）是嘌呤分解代谢的终产物，其血清水平在癌症患者中通常升高。我们旨在探索人肿瘤中肿瘤尿酸生成的转录调控，并将尿酸生成与肿瘤病理和药理学发现联系起来。利用来自癌症基因组图谱（TCGA）的数据，我们分析了黄嘌呤脱氢酶（XDH）和腺嘌呤磷酸核糖基转移酶（APRT）的表达水平，这两种酶分别是 UA 产生和嘌呤补救途径的关键酶。我们发现肿瘤类型和个体肿瘤之间在 和 的表达上存在很大差异。基因座特异性 DNA 甲基化和基因拷贝数的变化分别与人类肿瘤中 和 的表达水平相关。我们探讨了这种尿酸生成差异调节的后果。高 mRNA 水平的肿瘤的特点是编码促炎和免疫细胞因子的几个基因的表达更高，并且肿瘤浸润免疫细胞的水平增加。最后，我们使用国家癌症研究所-60（NCI-60）数据库中的数据研究了癌症药物敏感性。发现 和细胞对化疗药物 5-氟尿嘧啶（5-FU）的敏感性之间存在特定的相关性。我们的研究结果强调了不同类型人肿瘤之间尿酸生成存在巨大差异。尿酸生成的研究为鉴定临床相关的分子生物标志物和肿瘤分层提供了有希望的前景。
