Identifying neutrophil-associated subtypes in ulcerative colitis and confirming neutrophils promote colitis-associated colorectal cancer

Abstract

BackgroundUlcerative colitis (UC) is a chronic inflammatory disease of the intestinal mucosa, the incidence of which has increased worldwide. There is still a lack of clear understanding of the pathogenesis of ulcerative colitis that ultimately leads to colitis-associated colorectal cancer.MethodWe download UC transcriptome data from the GEO database and pass the limma package in order to identify differentially expressed genes. Gene Set Enrichment Analysis (GSEA) was used to identify potential biological pathways. We identified immune cells associated with UC by CIBERSORT and Weighted co-expression network analysis (WGCNA). We used validation cohorts and mouse models to verify the expression of the hub genes and the role of neutrophils.ResultWe identified 65 differentially expressed genes in UC samples and healthy controls. GSEA, KEGG, and GO analyses displayed that DEGs were enriched in immune-related pathways. CIBERSORT analysis revealed increased infiltration of neutrophils in UC tissues. The red module, obtained by WGCNA analysis, was considered to be the most relevant module for neutrophils.Based on neutrophil-associated differentially expressed genes, UC patients were classified into two subtypes of neutrophil infiltration. We discovered that the highly neutrophil-infiltrated subtype B of UC patients had a higher risk of developing CAC. Five genes were identified as biomarkers by searching for DEGs between distinct subtypes. Finally, using the mouse model, we determined the expression of these five genes in the control, DSS, and AOM/DSS groups. The degree of neutrophil infiltration in mice and the percentage of MPO and pSTAT3 expression in neutrophils were analyzed by flow cytometry. In the AOM/DSS model, MPO and pSTAT3 expressions were significantly increased.ConclusionsThese findings suggested neutrophils might promote the conversion of UC into CAC. These findings improve our understanding of the pathogenesis of CAC and provide new and more effective insights into the prevention and treatment of CAC.

The molecular subtypes of autoimmune diseases

“…The high inflammation subtype, identified in three studies [58] , [76] , [102] , is characterized by marked inflammatory features, including significant enrichment in inflammation and immune-related pathways such as interferon-γ/α response, TNF-α signaling pathway, IL-6 JAK-STAT3 signaling pathway [102] , and others including complement and coagulation cascades, cytokine-cytokine receptor interaction, and Toll-like receptor signaling pathway [76] . It also involves the upregulation of proinflammatory markers at the mRNA level, such as S100A8, S100A9, TNF-α, IL-1β, IL-6, IL-17, INF-γ.…”

“…NETs may also intensify autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus [75] . Thus, in a study on ulcerative colitis (UC) subtype study, researchers determined subtypes based on neutrophil-associated differential expression genes [76] . Initially, the limma [77] tool was used to identify DEGs between disease and normal controls.…”

Construction and multicohort validation of a colon cancer prognostic risk score system based on big data of neutrophil-associated differentially expressed genes

“…Daniel Triner et al suggested that neutrophils could impede colon tumor growth and progression by limiting bacterial populations and tumor-associated inflammatory responses 21 . Conversely, Zhang et al suggested that neutrophils might promote colitis-associated colon carcinogenesis 48 . Moreover, Rayes et al found evidence that NETs could facilitate targeted metastasis in colon cancer 49 .…”

6-Gingerol ameliorates ulcerative colitis by inhibiting ferroptosis based on the integrative analysis of plasma metabolomics and network pharmacology

“…UC has become a common digestive disease, and its recurrent episodes have been considered to increase the risk of colon cancer. 22 However, current treatment drugs for UC have limited their application due to their toxicity and side effects. 4 Consequently, dietary compounds are attracting more and more attention due to their advantages in treating diseases with fewer side effects.…”