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. 2023 Dec 4;15(23):5704.
doi: 10.3390/cancers15235704.

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

Taoufik Nedjadi  1 , Mohamed Eldigire Ahmed  2 , Hifzur R Ansari  1 , Sihem Aouabdi  1 , Jaudah Al-Maghrabi  3   4
Affiliations

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

Taoufik Nedjadi et al. Cancers (Basel). .

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.

Keywords: SPP1; bioinformatics; biomarker; bladder cancer; immune infiltration; prognostic.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Expression pattern of SPP1 in pan-cancer. (A) The expression of the SPP1 mRNA level in multiple TCGA cancers and matching normal tissues. p < 0.001, except Thym cancer (p = 0.7) and KICH cancer (p = 0.53). (B) Increased mRNA expression level of SPP1 in bladder cancer. (C) Promoter methylation status of SPP1 in bladder cancer and matching normal tissues. All data were analyzed using the UALCAN web tool.
Figure 2
Figure 2
Molecular alterations of SPP1 in cancers. (A) High amplifications/mutations of the SPP1 gene in bladder cancer compared other cancer types. (B) Positions and mutation frequency in SPP1 in bladder cancer.
Figure 3
Figure 3
Cytoplasmic expression of SPP1 in bladder carcinoma. Immunohistochemical staining of the bladder cancer tissue microarray using an SPP1 antibody. Figures showing: no expression (A,B), weak (C,D), moderate (E,F) and strong expression (G,H) of SPP1. Images were taken using 10× and 40× magnification objectives (scale bar equals 1 mm).
Figure 4
Figure 4
Nuclear SPP1 expression in bladder carcinoma. Immunohistochemical staining of the bladder cancer tissue microarray using an SPP1 antibody. Figures showing: no expression (C,D), and strong expression of SPP1 (A,B). Images were taken with 10× and 40× magnification objectives (scale bar equals 1 mm).
Figure 5
Figure 5
SPP1 expression and patients’ survival. Kaplan–Meier survival curve for bladder cancer patients expressing cytoplasmic (A) and nuclear (B) patterns of SPP1 (low expression vs. high expression). Low SPP1 immunostaining is associated with poor overall survival (log-rank p = 0.022).
Figure 6
Figure 6
Enrichment analysis of SPP1 in bladder cancer. (A) Identification of SPP1-interacting genes. Protein–protein interaction map and hub genes of SPP1. The size of the hub is proportional to the expression level. (B) Identification of the SPP1 co-expression network. The figure was generated using the online cBioPortal database. (C) KEGG functional enrichment analysis of SPP1. The figure was generated using the online cBioPortal database.
Figure 7
Figure 7
Correlation between immune cells and SPP1 expression. TIMER analysis of the correlation between SPP1 expression and immune cells’ infiltration. Purity-adjusted Spearman’s rho across various cell types by different algorithms.
Figure 8
Figure 8
Relationship between SPP1 expression and immune checkpoint genes in bladder cancer. (A) Correlation analysis between SPP1 expression and immune checkpoint genes. (B) The expression of immune checkpoint genes in relation to SPP1 expression. Data were analyzed using the cBioPortal cancer genomics website on TCGA data. The p-value significance codes: *** ≤0.001, ** ≤0.01, * ≤0.05.
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