Establishment of a Gene Expression Signature for Colitis-Associated Colorectal Cancer to Assess Cancer-Promoting Effects of Standard IBD Treatments

Background: Inflammatory bowel disease, particularly ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract that can progress to colitis-associated colorectal cancer. In addition to disease-related risk, certain pharmacological therapies used in UC management may further increase the likelihood of malignancies, including colorectal cancer. This study was conducted to identify novel biomarkers associated with carcinogenesis and early detection of CAC in patients with ulcerative colitis, using integrative bioinformatics approaches. Methods: Differential gene expression analysis was performed on microarray datasets. Genes commonly dysregulated in UC, sporadic colorectal cancer, and CAC, as well as CAC-specific genes, were identified as potential biomarkers. The expression levels of selected candidate genes were subsequently quantified by quantitative real-time PCR in colonic tissue samples obtained from UC patients receiving the studied pharmacological treatments, untreated UC patients, and healthy control individuals. Results: The genes SERPINE1 , COL1A1 , MMP9 , IL1B , ANXA5 , CAV1 , TLR2 , and VCAM1 were selected as candidate biomarkers. Long-term use of 5-aminosalicylic acid for more than five years resulted in a significant upregulation of COL1A1 , ANXA5 , and VCAM1 . Treatment with corticosteroids and immunomodulatory agents significantly increased the expression of IL1B and SERPINE1 , whereas anti-TNF therapy led to a significant increase only in CAV1 expression. Conclusions: Anti-TNF therapy was associated with significant upregulation of CAV1 , a gene involved in membrane signaling, endothelial integrity, and inflammatory regulation, and uniquely showed reduced expression of pro-inflammatory and adhesion-related genes such as IL1B and VCAM1 compared with untreated patients. In contrast, long-term treatment with 5-ASA, corticosteroids, and immunomodulatory agents did not reduce the expression of any analyzed genes and instead increased the expression of multiple candidates. These treatments were characterized by upregulation of IL1B , SERPINE1 , COL1A1 , MMP9 , ANXA5 , TLR2 , and VCAM1 suggest amplified inflammatory cell infiltration and epithelial damage, creating a microenvironment conducive to chronic inflammation, disease recurrence, and progression toward colitis-associated colorectal cancer. Overall, prolonged use of 5-ASA, corticosteroids, and immunomodulatory therapies appears to promote inflammation-driven carcinogenic pathways, limiting their suitability for long-term UC management, whereas anti-TNF therapy demonstrates a comparatively protective molecular profile by attenuating key inflammatory and immune pathways and may represent reduced contribution to CAC progression.