Integrative analysis of the SOX family-related prognostic signature and immunological infiltration in prostate cancer

Abstract

Background: Prostate cancer (PCa) remains a major prevalent cancer worldwide and has a poor prognosis. The sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) family is a series of transcription factors (TFs) involved in regulating many biological processes (BPs). In tumors, however, SOX genes are frequently deregulated. Tumorigenic deregulation took place at the transcriptional, translational, and posttranslational levels. This leads them to be correlated to tumor progression and poor clinical outcomes in PCa. Nevertheless, the SOX family prognostic role in PCa still needs further investigation.

Methods: A SOX family-related prognostic signature was developed by performing LASSO (Least absolute shrinkage and selection operator) Cox regression analysis. The construction of a lncRNA-miRNA-mRNA regulatory axis for PCa was performed using a ceRNA network.

Results: Upregulation was observed in the expression of SOX4/8/11/12/14, while downregulation was observed for SOX2/5/7/13/15/30 in PCa. Consensus clustering identified four clusters of PCa patients based on these differentially expressed SOX family members. The constructed SOX family-related prognostic signature, which includes five SOX family members (SOX5/8/11/12/30), performed well in predicting PCa-patient prognosis. B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cell immune infiltration levels had a significant association with PCa-patient risk scores. Based on additional analysis, a significant association was also suggested between SOX family expression and tumor mutational burden (TMB), microsatellite instability (MSI), and drug sensitivity. By constructing a ceRNA network, a lncRNA SGMS1-AS1/miR-194-5p/SOX5 regulatory axis was developed for PCa.

Conclusions: Herein, a SOX family-related prognostic signature was identified and was found to perform well in predicting PCa-patient prognosis. A lncRNA SGMS1-AS1/miR-194-5p/SOX5 regulatory axis was also identified for PCa progression.

Keywords: SOX family; SOX5; prognostic signature; prostate cancer (PCa).

Figure 1

SOX family gene expression in PCa. The SOX family mRNA level in PCa vs. normal prostate tissues. **, P<0.01; ***, P<0.001. SOX, sex-determining region Y-related high-mobility group box; PRAD, prostate adenocarcinoma; PCa, prostate cancer.

Figure 2

Consensus clustering analysis. (A,B) Consensus clustering matrix and relative change in area under the CDF curve for k=2-6. (C) The PCa cases distribution in consensus clustering. (D) Heatmap reveals the difference in the SOX family of these four clusters. (E) Survival curve of each cluster of PCa patients. CDF, cumulative distribution function; PCa, prostate cancer; SOX, sex-determining region Y-related high-mobility group box.

Figure 3

Disease-free survival analysis. (A) The forest plot revealed the results of the SOX family in the DFS analysis. (B-F) Survival curve in PCa patients with high/low SOX2/5/8/12/30 expressions. SOX, sex-determining region Y-related high-mobility group box; PCa, prostate cancer; DFS, disease-free survival; HR, hazard ratio, CI, confidence interval.

Figure 4

SOX family-related prognostic signature development. (A,B) The prognostic signature coefficient and partial likelihood deviance, as well as (C) risk score distribution, PCa case survival status, and gene expression profile. (D,E) Survival curve in the high/low-risk group and the ROC curve evaluating the predicting performance of PCa-patient prognosis. PCa, prostate cancer; SOX, sex-determining region Y-related high-mobility group box; ROC, receiver operating characteristic.

Figure 5

Risk score related to PCa immune infiltration. The association between the risk score and the expression of B cells (A), CD4+ T cells (B), CD8+ T cells (C), neutrophils (D), macrophage (E), and dendritic cells (F). PCa, prostate cancer.

Figure 6

The predictive nomogram development. (A,B) Univariate and multivariate Cox regression analyses regarding clinical parameters and the SOX family. (C,D) Predictive nomogram for predicting the 1-, 3-, and 5-year survival of PCa patients. The survival nomogram model calibration curve in the discovery group. A dashed diagonal line reflects the ideal nomogram. PCa, prostate cancer; SOX, sex-determining region Y-related high-mobility group box.

Figure 7

The correlation between the SOX family expression and IC50 drug sensitivity of CTRP. CTRP, cancer therapeutics response portal; SOX, sex-determining region Y-related high-mobility group box; FRD, false discovery rate.

Figure 8

Functional enrichment analysis of the SOX family in PCa. (A) The enriched items in GO analysis and (B) KEGG analysis. BP, biological process; CC, cellular component; MF molecular function; PCa, prostate cancer; SOX, sex-determining region Y-related high-mobility group box; GO, gene ontology; KEGG, kyoto encyclopedia of genes and genomes.

Figure 9

The correlation between each member of the differentially expressed SOX family in PCa. PCa, prostate cancer; SOX, sex-determining region Y-related high-mobility group box.

Figure 10

The lncRNA-miRNA-mRNA regulatory axis development. (A) PPI network identifying the hub gene. (B) The predicted miRNA targets via miRDB, miRWalk, and StarBase. (C) The miRNA target expressions in PCa. (D) The predicted lncRNA targets of miRNAs via lncBase and StarBase. (E) The lncRNA target expressions in PCa. (F) The lncRNA target prognostic values in PCa. *, P<0.05; ***, P<0.001; ****, P<0.0001. PCa, prostate cancer; SOX, sex-determining region Y-related high-mobility group box; PFS, progression-free survival; PPI, protein-protein interaction.

Figure 11

The expression of SOX family-related prognostic signature in PCa cell lines. The expression of SOX5 (A), SOX30 (B), SOX8 (C), SOX11 (D) and SOX12 (E) in PCa cell lines and RWPE-1. PCa, prostate cancer; SOX, sex-determining region Y-related high-mobility group box.