Unveiling prognostic value of JAK/STAT signaling pathway related genes in colorectal cancer: a study of Mendelian randomization analysis

Abstract

Background Colorectal cancer (CRC) ranks among the frequently occurring malignant neoplasms affecting the gastrointestinal tract. This study aimed to explore JAK-STAT signaling pathway related genes in CRC and establish a new prognostic model. Methods The data set used in this study is from a public database. JAK-STAT-differentially expressed genes (DEGs) were identified through differential expression analysis and weighted gene co-expression network analysis (WGCNA). Prognostic genes were selected from JAK-STAT-DEGs through Mendelian randomization (MR), univariate Cox regression, and least absolute shrinkage and selection operator (LASSO) analyses. The expressions of prognostic genes were verified by RT-qPCR. Then, a risk model was built and validated by the GSE39582. Independent prognostic factors were screened underlying risk scores and different clinical indicators, resulting in the construction of a nomogram. Additionally, immune infiltration, immune scores and immune checkpoint inhibitors analyses and gene set enrichment analysis (GSEA) were carried out. Results The 3,668 JAK-STAT-DEGs were obtained by intersection of 5,826 CRC-DEGs and 9,766 JAK-STAT key module genes. Five prognostic genes were selected (ANK3, F5, FAM50B, KLHL35, MPP2), and their expressions were significantly different between CRC and control groups. A risk model was constructed according to prognostic genes and verified by GSE39582. In addition, the nomogram exhibited superior predictive accuracy for CRC. Furthermore, immune analysis results indicated a notable positive correlation between risk score and the scores of immune (R = 0.486), stromal (R = 0.309), and ESTIMATE (R = 0.422). Immune checkpoint inhibitor ADORA2A (Cor = 0.483263) exhibited the strongest positive correlation with risk score. And MPP2 exhibited the most potent activating influence on the cell cycle pathway, whereas ANK3 demonstrated the most significant inhibitory effect within the apoptosis pathway. Conclusions A new JAK-STAT related CRC prognostic model was constructed and validated, which possessed an underlying predictive potential for CRC patients' prognosis and could potentially enhance tailored guidance for immunotherapy.