LB39
The role of wnt signalling in development of ulcerative colitis-associated colorectal carcinogenesis
Germaine Caldwell, Carolyn Jones, Glenn Matthews, Dion Morton
University of Birmingham, UK
Introduction
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) with multi-factorial aetiology. Patients with long-standing UC have an increased risk of developing colorectal cancer. Epigenetic silencing occurs in the colonic mucosa of chronic UC patients. Hypermethylation of the Wnt antagonist sFRP1 is a frequent, early event in sporadic colorectal carcinogenesis. Here, we describe our studies on Wnt signalling in UC colorectal carcinogenesis and assess its implication in tumour chemo-prevention.
Methods
Expression analysis was carried out using semi-quantitative Taqman real-time RT-PCR and promotor methylation status was determined using COBRA (COmbined Bisulphite Restriction Analysis).
Results
Data on a cohort of UC patients showed reduced sFRP1 expression, correlating with sFRP1 promotor hypermethylation apparently mimicking changes in early sporadic tumourigenesis. Normal tissue from acute UC patients (<6 months disease) and chronic UC patients (>10 years disease) showed no change in sFRP1 expression. In contrast, diseased and dysplastic tissue taken from the same chronic UC patients demonstrated a 10-fold down-regulation in sFRP1 expression that correlated with DNA hypermethylation. In chronic UC patients a 4.1-fold induction of NKD1, a ß-catenin transcriptional target was detected in dysplastic samples. In vitro treatment of cells with corticosteroids (often used in the treatment of UC) was shown to provoke the re-expression of Wnt antagonists.
Conclusion
This data suggests that major components of the Wnt signalling pathway, particularly FRP’s, could be used as biomarkers for neoplastic progression in IBD-related disease and suggests a possible mode of action for how current anti-inflammatory therapies may reduce cancer risk in UC patients.
