Keywords
Crohn’s disease
Mendelian randomization
NOD2
Immune infiltration
Submitted : 2025-12-09
Accepted : 2025-12-24
Published : 2026-01-08
Abstract
Background: Pancreatic cancer (PC) is a leading cause of cancer death worldwide, with early diagnosis being difficult and prognosis poor. Crohn’s disease (CD) is a chronic inflammatory bowel disease, and some studies suggest a potential link between CD and the development of pancreatic cancer. However, the exact biological mechanisms are unclear. This study investigates the causal relationship between CD and PC and focuses on the role of the NOD2 gene in pancreatic cancer. Methods: The study used Mendelian randomization (MR) to identify SNPs associated with both CD and PC, followed by functional annotation through the Ensembl database. Differential expression of these genes in pancreatic cancer was analyzed using the GEPIA2 platform. The study then used Metascape for gene enrichment and pathway analysis, and Kaplan-Meier Plotter to assess the relationship between gene expression and patient survival. Immunohistochemistry (IHC) was conducted to validate protein expression, and the TIMER 3.0 platform was used to examine immune cell infiltration related to NOD2. Finally, the study explored the relationship between NOD2 mRNA expression and clinical features using the cBioPortal platform. Results: Out of 91 candidate genes, 36 showed significant differential expression between pancreatic cancer and normal tissues. High expression of 9 genes was associated with poor prognosis. NOD2 was identified as a key gene with elevated expression in pancreatic cancer tissues, closely linked to immune cell infiltration. Further analysis showed that NOD2 expression correlated with tumor stage, lymph node metastasis, and distant metastasis, especially in advanced stages (T3, N1, Stage IIB). Conclusion: This study highlights the potential role of the NOD2 gene in linking Crohn’s disease with pancreatic cancer, suggesting that NOD2 may contribute to pancreatic cancer development through immune and inflammatory processes. Elevated NOD2 expression is associated with clinical features of pancreatic cancer, making it a potential prognostic marker. Future research should focus on understanding NOD2’s role in the immune microenvironment and its potential as a therapeutic target.
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