PURPOSE: CYLD is a tumor suppressor that has been linked to the development of 
various human malignancies, including colon cancer. The tumor-suppressing 
function of CYLD is associated with its deubiquitinating activity, which maps to 
the carboxyl-terminal region of the protein. In the present study we evaluated 
the role of intestinal epithelial CYLD in colitis-associated cancer using a 
conditional mouse CYLD inactivation model.
METHODS: In order to evaluate the role of CYLD in intestinal epithelial 
carcinogenesis, mice (IEC-Cyld (Δ9) mice) that carry a mutation that eliminates 
the deubiquitinating domain of CYLD in intestinal epithelial cells (IEC) were 
generated by crossing Villin-Cre transgenic mice to previously generated mice 
carrying a loxP-flanked Cyld exon 9 (Cyld (flx9) mice).
RESULTS: We found that IEC-Cyld (Δ9) mice did not present spontaneous intestinal 
abnormalities up to one year of age. However, upon challenge with a combination 
of genotoxic (AOM) and pro-inflammatory (DSS) agents we found that the number of 
adenomas in the IEC-Cyld (Δ9) mice was dramatically increased compared to the 
control mice. Inactivation of CYLD in intestinal epithelial cells did not affect 
the classical nuclear factor-kappaB (NF-κB) and c-Jun kinase (JNK) activation 
pathways under physiological conditions, suggesting that these pathways do not 
predispose CYLD-deficient intestinal epithelia to colorectal cancer development 
before the onset of genotoxic and/or pro-inflammatory stress.
CONCLUSIONS: Our findings underscore a critical tumor-suppressing role for 
functional intestinal epithelial CYLD in colitis-associated carcinogenesis. CYLD 
expression and its associated pathways in intestinal tumors may be exploited for 
future prognostic and therapeutic purposes.