Multi-Omics Analysis Reveals the Role of PFKFB3 as a Prognostic-Related Marker of Hypoxia in Pan-Cancer and Osteosarcoma

Background: According to many studies, the development of several tumors is significantly influenced by hypoxia-related indi-cators. However, the biochemical link between hypoxia markers and tumors, and their potential clinical implications, remain obscure.Methods: We obtained sequencing data and clinical information on osteosarcoma (OS) from the TARGET database and screened for hypoxia-associated genes linked with its poor prognosis. We then identified PFKFB3 as a potential biomarker using pan-cancer analysis. The expression pattern of PFKFB3 and its immunological role were comprehensively investigated using pan-cancer analysis. The PFKFB3 protein was then systematically correlated with tumor progression-related features such as TMB, MSI, CNV, hypoxia score, and metabolic pathways. We also analyzed the role of PFKFB3 in predicting OS molecular subtypes and identified potential PFKFB3 target drugs.Results: A total of 10 hypoxia-associated poor prognosis genes were screened from the OS dataset. By pan-cancer analysis, we found that PFKFB3 expression was positively associated with HIF1A in almost all tumor types. The overall survival was unfavor-able in pan-cancer patients with high levels of PFKFB3 in ACC, KIRP, LIHC, and UVM. Additionally, we found that PFKFB3 positively correlated with chemokines, chemokine receptors, and immune suppressive signatures in most cancers. Furthermore, a high percentage of activation of the EMT pathway was observed in pan-cancer cells possibly affected by PFKFB3. The expres-sion of PFKFB3 at the single-cell level was associated with hypoxia, metastasis, inflammation, and EMT in most tumors. Three distinct OS subtypes were identified using gene sets derived from genes positively related to PFKFB3 in the glycolytic, oxidative phosphorylation, and inflammatory signaling pathways. Drug sensitivity analysis showed that CH5424802 had the highest neg-ative correlation with PFKFB3.Conclusions: We described the characterization of PFKFB3 and its potential utility as a prognostic indicator in OS and other cancers.