Pan-cancer analysis of UDP-glucose 6-dehydrogenase in human tumors and its function in hepatocellular carcinoma.

Abstract

Background: UDP-glucose 6-dehydrogenase (UGDH) is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways.

Aim: To offer a more systematic and comprehensive elucidation of the involvement of UGDH in the onset and progression of various malignancies.

Methods: The role of UGDH in cancer was investigated via public databases. The data were analyzed via various R packages and websites, including TISIDB, cBioPortal, STRING, Cytoscape, GSCALite, and CancerSEA. A rat hepatocellular carcinoma (HCC) model was established via the intraperitoneal injection of diethylnitrosamine. Hematoxylin-eosin staining, Masson staining, Ki67 and UGDH immunohistochemical staining, and ARG1 immunofluorescence staining of liver tissues were performed. Real-time quantitative PCR and Western blotting were used to detect UGDH expression. The UGDH gene was knocked down in Huh7 cells, and CCK8 and nude mouse tumor xenograft assays were performed.

Results: High UGDH expression is associated with poor clinical outcomes in HCC, lung adenocarcinoma, lung squamous cell carcinoma, and sarcoma patients and is differentially expressed across molecular and immune subtypes. UGDH is primarily involved in the pentose and glucuronate interconversion pathway. Its expression is positively correlated with T helper, Tcm, and Th2 cells in most cancers. Moreover, experimental results demonstrated that UGDH expression is elevated in HCC tissues and that its downregulation inhibits HCC cell proliferation.

Conclusion: Our study revealed that UGDH could be a valuable prognostic biomarker and potential therapeutic target in many cancers, especially liver and lung cancer. UGDH could promote HCC cell proliferation, potentially by modulating the pentose and glucuronate interconversion pathways.