Abstract

Introduction Ulcerative colitis (UC) is an inflammatory disease characterized by colonic epithelial damage. With prolonged disease duration, the risk of malignant transformation increases significantly. However, the mechanisms driving the progression from chronic inflammation to tumorigenesis remain incompletely understood. This study aimed to identify a set of genes that may contribute to the transition from healthy controls (HC) to UC and ultimately to colitis-associated colorectal cancer (CAC). Methods We conducted bioinformatic analysis of four Gene Expression Omnibus (GEO) datasets to identify genes involved in the transitions from HC to UC and from UC to CAC. Functional enrichment and immune infiltration analyses were performed. Immunohistochemistry (IHC) validated the expression of key genes in UC patients. In vitro experiments assessed the effect of IFN- γ and TNF- α stimulation on PDL1 expression in neutrophils. Results Seven key genes—S100A8, IL33, MGP, MMP3, CFI, CLU, and CLEC4E—were upregulated during HC to UC and UC to CAC transitions. These genes were linked to neutrophils and pathways like Interferon (IFN)- γ , Tumor Necrosis Factor (TNF)- α and oxidative phosphorylation. Immunohistochemistry in mice confirmed expression levels, with five genes showing statistical significance. Additionally, IFN- γ and TNF- α stimulation significantly increased Programmed Death-Ligand 1 (PD-L1) expression in neutrophils. Conclusion We identified seven genes that are persistently upregulated during the progression from HC to UC and CAC. These genes influence neutrophils and inflammatory/tumorigenic pathways. The upregulation of PD-L1 in neutrophils suggests that neutrophil-mediated immune suppression may contribute to CAC progression, supporting their potential as molecular markers and therapeutic targets for early intervention in UC-related cancer.