Pan-Cancer Analysis Predicts FOXS1 as a Key Target in Prognosis and Tumor Immunotherapy

Abstract

Purpose: Only a few studies have reported the role of FOXS1, a transcriptional factor, in the tumor development process. In this article, we investigate the function of FOXS1 in distinct neoplastic development and the tumor immune microenvironment (TIME).

Patients and methods: The latent roles of FOXS1 in various tumors were prospected based on TCGA, GTEx, CCLE, GEPIA2, cBioPortal, TIMER, ImmuCellAI databases, GSVA datasets, GSEA datasets, and R packages. The expression difference, gene alteration, clinical characteristics, prognostic values, biological mechanism, potential pathways, tumor microenvironment, and immune cell infiltration related to FOXS1 were appraised.

Results: FOXS1 was strongly expressed in pan-cancer, and this gene was associated with low survival rates. FOXS1 was linked to many pathways that are cancer-promoting and immune-related. The expression of this transcriptional factor in cancers was positively related to immune cell infiltration, especially M2-like macrophages and Treg cells. In addition to that, FOXS1 demonstrated a positive relationship with many immune-suppression genes, such as TGFB1 and ARORA2A.

Conclusion: Our study identified an oncogenic effect of FOXS1, which may play a vital role as a prognosticative biological marker in pan-cancer. Exorbitant expression of FOXS1 is associated with high TAMs and Treg cells infiltration. These cells have an immunosuppressive function and promote the development of the immunosuppressive tumor microenvironment. The research of FOXS1 provided a potential drug target for tumor immunotherapy.

Keywords: FOXS1; M2-like macrophages; Treg cells; biological marker; immunosuppressive microenvironment; pan-cancer.

Figure 1

FOXS1 characteristics and its differential expression levels between cancer samples and normal body tissues. (A) Genomic location of the FOXS1 gene. (B–D) Mean transcriptional level of FOXS1 in normal tissues, TCGA, and tumor cell lines. (E) Expression levels of FOXS1 in cancer tissues and corresponding normal tissues. (F–K) FOXS1 transcript-level in different pathological stages in ACC, BLCA, BRCA, ESCA, KIRP, and KIRC. The data was log2 (transcripts per million [TPM] + 1) transformed, and only significant results were shown. (*p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001).

Figure 2

Genetic alternations of FOXS1 in different cancer types (cBioportal). (A) The alternation frequency of FOXS1 occurred in pan-cancer. (B) Correlations between DNA methylation and the mRNA level of FOXS1 (p < 0.05).

Figure 3

Relationship between FOXS1 level and OS. (A) The survival heat map from the GEPIA2 tool. (B–Q) Kaplan-Meier curves were used to characterize OS in pan-cancer. High expression of FOXS1 was associated with worse OS prognosis in ACC, CESC, COAD, ESCA, KICH, KIRC), KIRP, LAML, LGG, LICH, MESO, PAAD, SKCM, STAD, TCGT, and UVM. Only significant differences were indicated in the results. (R packages “survival” and “survminer”).

Figure 4

Prognostic value of FOXS1 based on TGCA dataset in various cancers. Univariate Cox regression analysis was used to analyze the correlation between FOXS1 mRNA expression and OS (A), PFI (B), DFI (C), DSS (D) across 33 tumors.

Figure 5

GSVA of FOXS1 in pan-cancer. The heatmap exhibits the relationship between FOXS1 expression and 50 Hallmark pathways. (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

Figure 6

Correlation analysis between FOXS1 and TME. Four radar charts show the relationship between FOXS1 expression and stromal scores (A), ESTIMATE scores (B), immune scores (C), Tumor purity (D). The heatmap exhibits the relationship between FOXS1 expression and ESTIMATE analysis (E). (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

Figure 7

Correlation between FOXS1 expression and TME-related biological processes. (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

Figure 8

Relationship between FOXS1 expression and different immune cells infiltration levels. Correlation between FOXS1 expression and different immune-related cells from TIMER2 database (A), ImmuCellAI database (B) a recent study (C). (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001).

Figure 9

Correlation between FOXS1 transcript-level and immune-related genes including MHC genes (A), immunosuppressive genes (B), chemokines (C), and chemokine receptors (D) (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).