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

Abstract

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 XDH high HCC tumors contained abundant infiltrating CD8\u2009+\u2009T 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.