Figure S3. (A) Representative immunostaining images of colonic mucosa of controls and patients with refractory UC using anti-Sox2 antibody. Scale bar, 50 microm. (B) Representative immunostaining images of colonic mucosa of patients with refractory UC with anti-Cirp and anti-E-cadherin antibodies. (C) Representative immunostaining images of well-moderately differentiated colorectal cancer tissues with anti-Cirp antibody. Scale bar, 100 microm. (D) Representative immunostaining images of colonic mucosa of patients with refractory UC using anti-Dclk1 antibody. Scale bar, 20 microm.
ARTICLE ABSTRACT
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 and CAC. In the colonic mucosa of patients with ulcerative colitis, expression of Cirp correlated significantly with the expression of TNFα, 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 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 TNFα, IL23, 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 TNFα, IL23/IL17, 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 TNFα and IL23 in inflammatory cells. Cancer Res; 74(21); 6119–28. ©2014 AACR.
