The Significance of Secreted Phosphoprotein 1 in Multiple Human Cancers

Abstract

Malignant tumor represents a major reason for death in the world and its incidence is growing rapidly. Developing the tools for early diagnosis is possibly a promising way to offer diverse therapeutic options and promote the survival chance. Secreted phosphoprotein 1 (SPP1), also called Osteopontin (OPN), has been demonstrated overexpressed in many cancers. However, the specific role of SPP1 in prognosis, gene mutations, and changes in gene and miRNA expression in human cancers is unclear. In this report, we found SPP1 expression was higher in most of the human cancers. Based on Kaplan-Meier plotter and the PrognoScan database, we found high SPP1 expression was significantly correlated with poor survival in various cancers. Using a large dataset of colon adenocarcinoma (COAD), head and neck cancer (HNSC), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC) patients from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, this study identified 22 common genes and 2 common miRNAs. GO, and KEGG paths analyses suggested that SPP1 correlated genes were mainly involved in positive regulation of immune cell activation and infiltration. SPP1-associated genes and miRNAs regulatory networks suggested that their interactions may play a role in the progression of four selected cancers. SPP1 showed significant positive correlation with the immunocyte and immune marker sets infiltrating degrees. All of these data provide strong evidence that SPP1 may promote tumor progress through interacting with carcinogenic genes and facilitating immune cells' infiltration in COAD, HNSC, LUAD, and LUSC.

Keywords: SPP1; biomarker; gene expression; immune infiltration; miRNA; multiple human cancers; tumor prognosis.

FIGURE 1

SPP1 levels in diverse cancer types and normal tissues. (A) High (red) or low (blue) SPP1 levels in various cancer types relative to non-carcinoma tissue samples based on the Oncomine database. (B) SPP1 expression in diverse cancers relative to the non-carcinoma tissue samples based on TCGA database was studied through TIMER. BLCA, bladder urothelial carcinoma; ACC, adrenocortical carcinoma; BRCA, breast invasive carcinoma; CHOL, cholangiocarcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; ESCA, esophageal carcinoma; COAD, colon adenocarcinoma; HNSC, head and neck cancer; GBM, glioblastoma multiforme; KIRC, kidney renal clear cell carcinoma; KICH, kidney Chromophobe; LIHC, liver hepatocellular carcinoma; KIRP, kidney renal papillary cell carcinoma; LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma; PAAD, pancreatic adenocarcinoma; OV, ovarian serous cystadenocarcinoma; READ, rectum adenocarcinoma; PRAD, prostate adenocarcinoma; THCA, thyroid carcinoma; STAD, stomach adenocarcinoma; UCEC, uterine corpus endometrial carcinoma; THYM, thymoma; UVM, uveal Melanoma; and UCS, uterine carcinosarcomas (**P < 0.01, ***P < 0.001).

FIGURE 2

Survival for diverse cancer types according to SPP1 level based on the Kaplan-Meier plotter (A–J) and PrognoScan databases (K–P). (A–J) The OS and RFS curves for BLCA (n = 404), CESC (n = 304), LIHC (n = 370), LUAD (n = 504), LUSC (n = 495), READ (n = 165), HNSC (n = 499 and n = 124) and PAAD cancer (n = 177 and n = 69). (K,L) Survival curves of OS in BRCA [GSE1456 (n = 159)] and COAD [GSE17536 (n = 177)]. (M,N) Survival curves of OS and RFS in LUAD [GSE31210 (n = 204) and GSE31210 (n = 204)]. (O,P) Survival curves of OS and DFS in LUSC [GSE4573, (n = 129) and GSE4573 (n = 56)]. RFS, relapse-free survival; OS, overall survival.

FIGURE 3

SPP1 correlated genomic alterations and genes in TCGA. Venn diagram depicting the distribution of SPP1 correlated genomic alterations (A) and genes (B) in COAD, HNSC, LUAD, and LUSC. (C) Correlation between SPP1 and CTSB, MMP12, and SULF1. HNSC, head and neck cancer; COAD, colon adenocarcinoma; LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma.

FIGURE 4

The expression and functional analyses of common genes based on TCGA. (A–D) Heatmap of SPP1 and 22 common genes expression in four types of cancers. Patients in four cancers were classified as high (red) or low (green) SPP1 group based on the median expression of SPP1. The gradual change from blue to red represents a gradual increase in gene expression. GO (E) as well as KEGG (F) analysis for the 134 common genes. HNSC, head and neck cancer; COAD, colon adenocarcinoma; LUSC, lung squamous cell carcinoma, and LUAD, lung adenocarcinoma.

FIGURE 5

The common gene expression (A) and the correlation between SPP1 and CTSB, MMP12 and SULF1 in GEO (B). High (red) or low (green) SPP1 expression group. The gradual change from blue to red represents a gradual increase in gene expression. HNSC, head and neck cancer; COAD, colon adenocarcinoma; LUSC, lung squamous cell carcinoma; and LUAD, lung adenocarcinoma. P < 0.05.

FIGURE 6

SPP1 correlated miRNA in TCGA and miRNA-gene regulatory network. (A) Venn diagram analysis of SPP1 correlated miRNA in COAD, HNSC, LUAD, LUSC. (B) The miRNA-gene regulatory network consists of 21 miRNAs and 71 genes. (C) The correlation between SPP1 and two common miRNAs. HNSC, head and neck cancer; COAD, colon adenocarcinoma; LUSC, lung squamous cell carcinoma; and LUAD, lung adenocarcinoma.

FIGURE 7

Relationship between SPP1 level and the mRNAsi and immune infiltrating degrees of COAD, HNSC, LUSC and LUAD. (A) The comparison of mRNAsi in high versus low SPP1 expression groups of different tumors. (B) Relationship between SPP1 levels and the immune infiltrating degrees of four selected cancer types. mRNAsi, mRNA expression based-stemness index; HNSC, head and neck cancer (n = 457); COAD, colon adenocarcinoma (n = 457); LUSC, lung squamous cell carcinoma (n = 507); LUAD, lung adenocarcinoma (n = 515).

FIGURE 8

Correlation of SPP1 with receptors. (A) Protein-protein interaction (PPI) network. 10 molecules with the highest correlation with SPP1. (B,C) Correlation analysis between SPP1 and CD44 and ITGB1 in COAD, HNSC, LUAD, and LUSC from GEPIA. COAD, colon adenocarcinoma (n = 275), COAD normal (n = 349); HNSC, head and neck cancer (n = 519), HNSC normal (n = 44); LUAD, lung adenocarcinoma (n = 483), LUAD normal (n = 347); LUSC, lung squamous cell carcinoma (n = 486), LUSC normal (n = 338).