Abstract
Backgrounds: Abnormalities in glycometabolism lead to carcinogenesis. UDP-glucose 6-dehydrogenase (UGDH) is the key enzyme of glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways. In this study, our objective is to offer a more systematic and comprehensive elucidation of the involvement of UGDH in the onset and advancement of various malignancies via an in-depth analysis of UGDH in cancer contexts.
Method: We investigated the role of UGDH in cancers using the Human Protein Atlas (HPA), The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) databases. And analyzed data using various R packages and websites, including TISIDB, cBioPortal, STRING, Cytoscape, GSCALite, and CancerSEA. A rat hepatocellular carcinoma (HCC) model was established using intraperitoneal injection of diethylnitrosamine. Hematoxylin-Eosin (HE) staining, MASSON staining, and KI67 immunohistochemistry of liver tissues were performed. Real-time quantitative PCR (qRT-PCR) and western blotting (WB) were used to detect the expression of UGDH. UGDH gene was knocked down in Huh7 cells, and CCK8 and nude mice tumor xenograft assays were further performed.
Results: UGDH high expression is associated with poor clinical outcomes in hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, and sarcoma. And differentially expressed across molecular and immune subtypes. UGDH was primarily involved in the pentose and glucuronate interconversion pathway. Its expression positively correlated with T helper, Tcm, and Th2 cells in most cancers. Moreover, experimental results demonstrated that UGDH expression is elevated in liver cancer and promotes the proliferation of HCC.
Conclusions: Our study elucidates that UGDH could be used as a valuable prognostic biomarker and potential therapeutic target in many cancers, especially liver and lung cancer. UGDH could promote the proliferation of HCC cells, possibly by modulating the pentose and glucuronate interconversion pathway.