A pan-cancer study of the transcriptional regulation of uricogenesis in human tumours: pathological and pharmacological correlates

Saidak, Zuzana; Louandre, Christophe; Dahmani, Samy; Sauzay, Chloé; Guedda, Sara; Chauffert, Bruno; Chatelain, Denis; Ceballos-Picot, Irène; Galmiche, Antoine

doi:10.1042/bsr20171716

Cited by 9 publications

(8 citation statements)

References 39 publications

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“…Although there was a significant positive correlation between XDH expression and macrophage infiltration in the TIMER database, only a positive trend was found between XDH expression and CD68 + macrophage infiltration in this small group of HCC tissues. Indeed, Saidak et al indicated that XDH expression is linked to an immune infiltrate in tumors [55]. XDH expression initiates several immune-related pathways, including the T cell receptor, PI3K-AKT, and MAPK signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma

et al. 2021

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Background Xanthine dehydrogenase (XDH) is a critical enzyme involved in the oxidative metabolism of purines, pterin and aldehydes and a central component of the innate immune system. However, the prognostic value of XDH in predicting tumor-infiltrating lymphocyte abundance, the immune response, and survival in different cancers, including hepatocellular carcinoma (HCC), is still unclear. Methods XDH expression was analyzed in multiple databases, including Oncomine, the Tumor Immune Estimation Resource (TIMER), the Kaplan–Meier plotter database, the Gene Expression Profiling Interactive Analysis (GEPIA) database, and The Cancer Genome Atlas (TCGA). XDH-associated transcriptional profiles were detected with an mRNA array, and the levels of infiltrating immune cells were validated by immunohistochemistry (IHC) of HCC tissues. A predictive signature containing multiple XDH-associated immune genes was established using the Cox regression model. Results Decreased XDH mRNA expression was detected in human cancers originating from the liver, bladder, breast, colon, bile duct, kidney, and hematolymphoid system. The prognostic potential of XDH mRNA expression was also significant in certain other cancers, including HCC, breast cancer, kidney or bladder carcinoma, gastric cancer, mesothelioma, lung cancer, and ovarian cancer. In HCC, a low XDH mRNA level predicted poorer overall survival, disease-specific survival, disease-free survival, and progression-free survival. The prognostic value of XDH was independent of the clinical features of HCC patients. Indeed, XDH expression in HCC activated several immune-related pathways, including the T cell receptor, PI3K-AKT, and MAPK signaling pathways, which induced a cytotoxic immune response. Importantly, the microenvironment of XDHhigh HCC tumors contained abundant infiltrating CD8 + T cells but not exhausted T cells. A risk prediction signature based on multiple XDH-associated immune genes was revealed as an independent predictor in the TCGA liver cancer cohort. Conclusion These findings suggest that XDH is a valuable prognostic biomarker in HCC and other cancers and indicate that it may function in tumor immunology. Loss of XDH expression may be an immune evasion mechanism for HCC.

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Section: Discussionmentioning

confidence: 99%

Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma

et al. 2021

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“…Recently, FTCD was found to be associated with the sensitivity of chemotherapeutic drug methotrexate by using a CRISPR-Cas9-based screen [ 32 ]. XDH, a rate-limiting enzyme to catalyze the final steps of purine metabolism, was found significantly decreased and served as a useful predictor of poor prognoses in several cancer types [ 33 ]. Uric acid, which was transformed by XDH, was found to modulate tumor cell sensitivity to the antimetabolite 5-FU, one of the most commonly used anticancer drugs in the clinic [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Development of a KRAS-Associated Metabolic Risk Model for Prognostic Prediction in Pancreatic Cancer

et al. 2021

BioMed Research International

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Background. KRAS was reported to affect some metabolic genes and promote metabolic reprogramming in solid tumors. However, there was no comprehensive analysis to explore KRAS-associated metabolic signature or risk model for pancreatic cancer (PC). Methods. In the current study, multiple bioinformatics analyses were used to identify differentially expressed metabolic genes based on KRAS mutation status in PC. Then, we developed and validated a prognostic risk model based on the selected KRAS-associated metabolic genes. Besides, we explored the association between the risk model and the metabolic characteristics as well as gemcitabine-associated chemoresistance in PC. Results. 6 KRAS-associated metabolic genes (i.e., CYP2S1, GPX3, FTCD, ENPP2, UGT1A10, and XDH) were selected and enrolled to establish a prognostic risk model. The prognostic model had a high C-index of 0.733 for overall survival (OS) in TCGA pancreatic cancer database. The area under the curve (AUC) values of 1- and 3-year survival were both greater than 0.70. Then, the risk model was validated in two GEO datasets and also presented a satisfactory discrimination and calibration performance. Further, we found that the expression of some KRAS-driven glycolysis-associated genes (PKM, GLUT1, HK2, and LDHA) and gemcitabine-associated chemoresistance genes (i.e., CDA and RMM2) was significantly upregulated in high-risk PC patients evaluated by the risk model. Conclusions. We constructed a risk model based on 6 KRAS-associated metabolic genes, which predicted patients’ survival with high accuracy and reflected tumor metabolic characteristics and gemcitabine-associated chemoresistance in PC.

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“…A recent study suggested that XDH expression levels are associated with tumor growth. Elevated expression of XDH is associated with tumor infiltration as well as upregulated proinflammatory and immune-related cytokine expression [31]. XDH also served as a useful biological parameter in a pan-cancer study [31], but its molecular function in neuronal or other cells remains largely unexplored given that it may be either reversibly or irreversibly converted to XO in mammals [32,33].…”

Section: Y P E X D H -1 ( C H R 1 ) X D H -1 ( O K 3 2 3 4 ) X D H -1 ( C H R 1 ) ; E X [ X D H -1 G E N E ] X D H -1 ( O K 3 2 3 4 ) ; Ementioning

confidence: 99%

“…Elevated expression of XDH is associated with tumor infiltration as well as upregulated proinflammatory and immune-related cytokine expression [31]. XDH also served as a useful biological parameter in a pan-cancer study [31], but its molecular function in neuronal or other cells remains largely unexplored given that it may be either reversibly or irreversibly converted to XO in mammals [32,33]. In contrast, since invertebrate XOR is present only as XDH [33], C. elegans is thought to be a useful model for studying XDH.…”

Section: Y P E X D H -1 ( C H R 1 ) X D H -1 ( O K 3 2 3 4 ) X D H -1 ( C H R 1 ) ; E X [ X D H -1 G E N E ] X D H -1 ( O K 3 2 3 4 ) ; Ementioning

confidence: 99%

The mechanoreceptor DEG‐1 regulates cold tolerance in Caenorhabditis elegans

et al. 2020

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Caenorhabditis elegans mechanoreceptors located in ASG sensory neurons have been found to sense ambient temperature, which is a key trait for animal survival. Here, we show that experimental loss of xanthine dehydrogenase (XDH‐1) function in AIN and AVJ interneurons results in reduced cold tolerance and atypical neuronal response to changes in temperature. These interneurons connect with upstream neurons such as the mechanoreceptor‐expressing ASG. Ca2+ imaging revealed that ASG neurons respond to warm temperature via the mechanoreceptor DEG‐1, a degenerin/epithelial Na+ channel (DEG/ENaC), which in turn affects downstream AIN and AVJ circuits. Ectopic expression of DEG‐1 in the ASE gustatory neuron results in the acquisition of warm sensitivity, while electrophysiological analysis revealed that DEG‐1 and human MDEG1 were involved in warm sensation. Taken together, these results suggest that cold tolerance is regulated by mechanoreceptor‐mediated circuit calculation.

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A pan-cancer study of the transcriptional regulation of uricogenesis in human tumours: pathological and pharmacological correlates

Cited by 9 publications

References 39 publications

Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma

Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma

Development of a KRAS-Associated Metabolic Risk Model for Prognostic Prediction in Pancreatic Cancer

The mechanoreceptor DEG‐1 regulates cold tolerance in Caenorhabditis elegans

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