Identification of SPP1 as a Prognostic Biomarker and Immune Cells Modulator in Urothelial Bladder Cancer: A Bioinformatics Analysis

Simple Summary Bladder cancer (BC) is one of the most common urological cancers affecting more men than women. The absence of biomarkers for early detection and prognostication add to the burden of the disease. The SPP1 protein is differentially expressed in many malignancies and could serve as a potential prognostic biomarker. However, its expression profile, clinical significance and prognostic value, as well as its relationship with immune infiltration, have not been comprehensively studied in bladder cancer. Herewith, we aimed to investigate the prognostic value of SPP1 expression and its association with other cancer-promoting factors in bladder cancer. Our data indicated that SPP1 is differentially expressed at an early stage of BC development and is associated with an unfavorable prognosis. Interaction between SPP1 and other proteins/genes and immune cell infiltrates may play an important role in the pathogenesis and could as a potential therapeutic target for bladder cancer.Abstract Secreted phosphoprotein-1 (SPP1) expression is differentially altered in many malignancies and could serve as a potential prognostic biomarker. Recent findings indicated that SPP1 possesses a broader role in bladder cancer (BC) pathogenesis than previously envisioned; however, the underlying mechanisms governing its expression, cellular localization, prognostic value and immune-related role in bladder cancer remain poorly understood. The expression and the prognosis value of SPP1 were assessed using immunohistochemistry (IHC) staining on a tissue microarray. SPP1 expression was correlated with the clinicopathological parameters, and survival analysis was calculated using a Kaplan-Meier plotter. Bioinformatics analysis of TCGA data was queried using UALCAN, CIBERSORT and TIMER datasets to decipher the biological processes enrichment pattern, protein-protein interactions and characterize tumor-infiltrating immune cells, respectively. IHC revealed that SPP1 expression is significantly associated with tumor type, stage, grade and smoking status. The Kaplan-Meier survival curve showed that low SPP1 expression is an unfavorable prognostic indicator in bladder cancer patients (p = 0.02, log-rank). The significant increased expression of the SPP1 level is associated with evident hypomethylation of the gene promoter in cancer compared to normal tissues in the TCGA-bladder dataset. Missense mutation is the most frequent genetic alteration of the SPP1 gene. Protein-protein interactions demonstrated that SPP1 shares the same network with many important genes and is involved in many signaling pathways and biological processes. TIMER reported a significant correlation between SPP1 expression and multiple immune cells infiltration. Furthermore, the expression of SPP1 was found to be positively correlated with a number of immune checkpoint genes such as PD-1 and CTLA4. The current investigation indicates that the SPP1 protein could serve as a prognostic biomarker and merit further investigation to validate its clinical usefulness in patients with bladder cancer.