CXCR6 and its correlated G protein-coupled receptors and PI3K-AKT pathways were associated with the progression of thyroid cancer

Abstract

Immunogenic cell death (ICD) is closely linked to thyroid cancer (THCA). We mined ICD-linked prognostic genes for survival predictors and unpacked their potential biology. Single-cell analysis was conducted to identify distinct cell types, and the scores of ICD-related genes (ICDRGs) were computed to identify key cell types. Furthermore, correlation, differential expression, and Kaplan-Meier survival studies were conducted to discover prognostic genes. By employing these genes alongside 101 combinations of 10 algorithms, we constructed a prognostic model and computed risk scores for THCA samples, analyzing their survival disparities. Control and THCA tissue samples were taken to assess the expression of prognostic genes via real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), resulting in the identification of a key gene. Subsequently, gene set enrichment analysis was executed on this key gene, and Western blot analysis was undertaken to evaluate the expression of relevant pathways. Single-cell and transcriptome analysis found CXCR6, ICOS, SLAMF7, CD80, and TNF as prognostic genes associated with ICD in THCA. Of the 101 combinations evaluated, the StepCox[both] + Random Survival Forest (RSF) model was selected as the prognostic model owing to its superior C-index. This model accurately forecasted survival outcomes for THCA samples. Expression study demonstrated a notable decrease of CXCR6 in THCA samples, consistent with bioinformatics analysis and it was designated as the key gene. Functional analysis revealed an enrichment of the inflammatory response, accompanied by reduced levels of its principal targets (Gαi) and downstream pathways (Src and PI3K-AKT) in THCA samples. This study found five prognostic genes, with CXCR6 associated with Gαi, Src, and PI3K-AKT pathways in the modulation of THCA, indicating the essential function of CXCR6 in THCA.