P062. The effect of steroids on expression of Wnt pathway inhibitors in patients with longstanding ulcerative colitis
G. Caldwell1, C. Jones1, G. Matthews1, I. Williams2, D. Morton2, T. Iqbal2
1University of Birmingham, Cancer Studies, Birmingham, United Kingdom; 2University Hospital Birmingham, Gastroenterology, Birmingham, United Kingdom
Background: Individuals with long-standing ulcerative colitis (UC) have an increased risk of colorectal cancer. Increasing epigenetic-associated silencing of the Wnt antagonists (sFRP's and WIF1) occurs in colorectal epithelium from UC and is associated with progression from colitis-dysplasia-cancer suggesting it is an early event in tumourigenesis. Longitudinal cohort studies indicate that the use of anti-inflammatory agents (corticosteroids and 5‑aminosalicylates) is chemoprotective, reducing cancer risk. The exact molecular mechanism of these effects is unknown.
Methods: Wnt antagonist mRNA expression was measured using quantitative real-time RT-PCR in cells and UC patient biopsies before and after treatment with steroids. Laboratory analysis was blinded to the treatment received.
Results: We present in vitro data demonstrating that corticosteroids increase the expression of the key Wnt antagonist's sFRP1, sFRP2 and sFRP4. Preliminary data from a phase II trial shows that sFRP1 expression is restored in 4 out of 5 UC patients following 4 weeks' steroid treatment. sFRP1 upregulation coincides with increased expression of the related Wnt antagonists sFRP2, sFRP4 and WIF1 in 3 of these patients. In 2 out of 2 untreated patients there is no change in sFRP1 expression. Investigations into the mechanism of the glucocorticoid induction are on-going.
Conclusions: This preliminary data suggests that topical steroid therapy may affect the expression of colonic epithelial Wnt inhibitor proteins in patients with longstanding UC and so ameliorate cancer risk.