The Role of mTOR/Stat3 in Tumorigenesis in Chronic Ulcerative Colitis
Q Liu, J Hart, K Tanaka, M Bissonnette, E Lin. Montefiore Medical Center of Albert Einstein College of Medicine, New York, NY; The University of Chicago Medical Center, Chicago, IL
Background: The pathogenesis of inflammatory bowel diseases (IBD) is thought to involve modulation of the intestinal mucosal immune response determined by a complex interplay of genetic, microbial and environmental factors. However, our mechanistic understanding of the link between inflammation and tumorigenesis in the colon is limited.
Design: This study was designed to characterize differences in gene expression in colonic mucosa between normal (n= 5 patients) and chronic ulcerative colitis (UC) patients with or with dysplasia (N=17 patients). A newly established mouse model of colitis-associated colorectal cancer, the Stat3-IKO mouse, was used to identify potential key tumor-promoting factors and determine the function of these factors identified in patients with chronic ulcerative colitis.
Results: Our studies demonstrated that mTOR/Stat3 pathway was activated in colonic epithelial cells in both human chronic colitis (UC) and the mouse model. Using the mouse model of colitis-associated colorectal cancer, we found that activation of mTOR/Stat3 pathway is specifically induced by inflammation and was associated with disruption of colonic homeostasis, fulminant epithelial/tumor cell proliferation and tumorigenesis in the inflamed colon. In the colonic mucosa of patients with chronic UC and dysplasia, there is an enhanced anti-microbial reaction similar to that observed in the mouse model. Upregulation of proinflammatory cytokines, CXCL10, CXCL11 and CCL9, and a repression of IL-17 signaling was observed in the mucosa of UC patients with dysplasia elsewhere in their colon, when compared to normal mucosa or UC mucosa without dysplasia. Cytokines whose activities are mediated by CXCR3 and CCR7 were markedly up-regulated in the inflamed colonic mucosa in Stat3-IKO mice. These findings suggest that the mTOR/Stat3 pathway is important in the development of IBD and dysplasia.
Conclusions: The activation of mTOR/Stat3 pathway in colonic epithelial cells, specifically induced by inflammation, may play a critical role in promoting tumorigenesis in ulcerative colitis. Several cytokine/chemokine pathways assoicated with antimicrobial function were found abnormally regulated in both human ulcerative colitis and inflamed colon of mouse. The future study is to identify the mechanistic link between dysregulated mucosa immunity and activation of the oncogenic pathway, mTOR/Stat3.
Category: Pan-genomic/Pan-proteomic Approaches to Diseases
Monday, March 22, 2010 1:00 PM
Poster Session II # 230, Monday Afternoon