Regulatory T Cell-Mediated IL-2-STAT5-Foxp3 Pathway may Predict the Prognosis of Patients with Cervical Cancer: A Gene Set Variation Analysis and Verification Study

Abstract

Cervical cancer has the highest incidence rate among gynaecological cancers. The treatment of advanced and recurrent cervical cancer is limited. Therefore, it is imperative to find new prognostic indicators and therapeutic targets. The main purpose of this study was to identify gene sets or pathways related to prognosis and explore their underlying mechanism. The samples were taken from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Gene Set Variation Analysis (GSVA) was used to score gene sets in tumor tissue and normal cervical tissue, and the samples were then grouped according to score and overall survival. A prognostic model with lasso regression was then undertaken. Gene Set Enrichment Analysis (GSEA) was used to analyse the function and pathway of gene sets. The Timer 2.0 database was used to explore the relationship between the expression of the gene set and the immune microenvironment. The Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database was used to verify the above results and showed the difference in the expression of hub genes in the gene set between cervical cancer and normal cervical tissue. Our study analysed 4922 gene sets, which were compared between 306 tumor tissue and 13 normal cervical tissue samples. The samples were divided into three subtypes, and the tumor grade was closely related to the subtypes. Hallmark-epithelial esenchymal (HR: 38.13;95% CI: 2.13-681.35;p = 0.013), Hallmark-angiogenesis (HR: 521.78;95% CI: 13.47-20210.87;p = 0.001) and GSE36888_untreated vs IL-2 treated STAT A/B T-cell IL-2 (HR: 1828.94;95% CI: 4.59-728605.07;p = 0.014) were found to be significant pathways related to prognosis through GSVA. In GSEA, the gene sets were enriched in response to lipopolysaccharide, response to molecule of bacterial origin and cytokine receptor binding, cytokine-cytokine receptor interaction, chemokine signaling pathway, IL-17 signaling pathway and viral protein interaction. We further analysed the IL-2-STAT5-Foxp3 pathway. The hub genes of this pathway were significantly enriched in regulatory T cells (Tregs), p < 0.05. IL-2R and Foxp3 were upregulated in cancer tissue compared to normal cervix (p < 0.01). In conclusion, IL-2-STAT5-Foxp3 may regulate Tregs in the immune environment, affecting the prognosis of cervical cancer.