SIR Medicine Investigation Abstract
5ASA SUPPRESSED INDUCTION OF DYSPLASIA ON AOM/DSS MODEL: CORRELATION WITH INHIBITION OF WNT/BETA-CATENIN TRANSCRIPTIONAL ACTIVITY
Presenter:
Vyas Viswanathan, Illinois Mathematics and Science Academy, 1500 W. Sullivan Road, Aurora, IL 60506
Mentor:
Mr. Gery Grimm, Northwestern University Medical Center
Abstract:
Patients with ulcerative colitis (UC), a form of inflammatory bowel disease (IBD), have increased risks of developing colorectal cancer (CRC). 5-aminosalicyilic acid (5ASA) is hypothesized to lower risks of developing CRC in IBD patients. This study shows the effects of high dose (HD) and low dose (LD) 5ASA in mice induced with CRC using the DSS/AOM model. After 3 cycles of DSS, 66% of the mice were observed to have high grade dysplasia, which was reduced by 14% subsequent to treatment with LD (100 mg/kg/d) 5ASA chow, while HD 5ASA (300mg/kg/d) reduced the instance of dysplasia in mice by 55%. Staining for epithelial BrdU incorporation (2h label) and Ki67 (cell cycle marker) within 3 days of DSS cessation showed that crypt cell proliferation increased by 200-300% compared to control groups without inflammation. Inflammation went down (7-14 days after DSS) with epithelial proliferation decreasing by >80% and the appearance of dysplastic crypts increasing. Isolation of colonic crypt epithelial cells 10 days after DSS showed significant increases (mRNA fold induction) in Wnt/ß-catenin target genes: cMyc and cyclin D1. Experiments showed a 70% reduction in cMyc induction and no effect for cyclin D1 using LD 5ASA, but experiments with HD 5ASA revealed a complete recession in cMyc and 82% reduction in cyclin D1. In conclusion, the data suggests that 5ASA reduces dysplastic transformation by inhibiting proximal signaling events needed for induction of inflammation-induced Wnt/ß-catenin transcriptional activity.