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

Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and is 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 andCAC. In the colonic mucosa of patients with ulcerative colitis, expression of Cirp correlated significantly with the expression of TNFa, IL23/IL17, antiapoptotic 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 ulcerative colitis, suggesting that Cirp expressionmight be related to increased cancer risk. In humanCACspecimens, inflammatory cells expressed Cirp protein. Cirp / mice given dextran sodium sulfate exhibited decreased susceptibility to colonic inflammation through decreased expression of TNFa, IL23, Bcl-2, and Bcl-xL in colonic lamina propria cells compared with similarly treatedwild-type (WT)mice. In themurine CACmodel, Cirp deficiency decreased the expression of TNFa, IL23/IL17, Bcl-2, Bcl-xL, and Sox2 and the number of Dclk1þ 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 TNFa and IL23 in inflammatory cells. Cancer Res; 74(21); 6119–28. 2014 AACR.