Stress Response Protein Cirp Links Inflammation and Tumorigenesis in Colitis-Associated Cancer

Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and reported to be associated with refractory inflammatory bowel disease (IBD). Defective apoptosis of inflammatory cell populations seems to be a relevant pathogenetic mechanism in refractory IBD. We assessed the involvement of stress response protein cold-inducible RNA-binding protein (Cirp) in the development of intestinal inflammation and CAC. In the colonic mucosa of ulcerative colitis (UC) patients, expression of Cirp correlated significantly with the expression of TNF-α, IL-23/IL-17, anti-apoptotic proteins Bcl-2 and Bcl-xL and stem cell markers such as Sox2, Bmi1 and Lgr5. The expression of Cirp and Sox2 was enhanced in the colonic mucosae of refractory UC, suggesting that Cirp expression might be related to increased cancer risk. In human CAC specimens, inflammatory cells expressed Cirp protein. Cirp-/- mice given dextran sodium sulfate exhibited decreased susceptibility to colonic inflammation through decreased expression of TNF-α, IL-23, Bcl-2 and Bcl-xL in colonic lamina propria cells compared with similarly treated wild type (WT) mice. In the murine CAC model, Cirp deficiency decreased the expression of TNF-α, IL-23/IL-17, Bcl-2, Bcl-xL and Sox2 and the number of Dclk1+ cells, leading to attenuated tumorigenic potential. Transplantation of Cirp-/- bone marrow into WT mice reduced tumorigenesis, indicating the importance of Cirp in hematopoietic cells. Cirp promotes the development of intestinal inflammation and colorectal tumors through regulating apoptosis and production of TNF-α and IL-23 in inflammatory cells.