This R03 Cancer Prevention Research grant application is being submitted in response to Program announcement (PA) number: PAR-08-055. Funding is being requested for validating the contribution of the transcription factor STAT2 in colorectal tumorigenesis. Our approach is to use a unique strain of the multiple intestinal neoplasia (Apc+/Min) mice generated at Fox Chase Cancer Center. These mice develop spontaneously significant number of colorectal adenomas and;therefore, are a suitable animal model to investigate STAT2 influence on colorectal tumorigenesis. While it is accepted that other members of the STAT family play active roles in the development of human cancer, it remains unclear what is the exact function of STAT2 in tumorigenesis. STAT2 is a transcription factor known for mediating the antiproliferative and apoptotic effects of type I interferons thus suggesting that STAT2 may operate as a tumor suppressor. However, results from our recent study contradict this view as we discovered that STAT2 was required in the promotion of colorectal carcinogenesis. In a mouse model of colitis associated cancer, compared to wild type mice, we found that STAT2-/- mice were more resistant to the combinatorial carcinogenic effects of azoxymethane and dextran sodium sulfate. STAT2-/- mice showed prolonged survival, developed fewer adenomas and the size of the lesions was smaller;all indicative of a delay in tumor progression. In addition, STAT2 enhanced STAT3 activation and secretion of pro-inflammatory IL-6, a multifunctional cytokine recently reported to be a critical tumor promoter during early colitis associated tumorigenesis. Consequently, our studies have uncovered STAT2 as a potential molecular target in the chemoprevention of colorectal cancer. The purpose of this grant application is to validate the tumor promoting effects of STAT2 in a distinct animal model of colorectal cancer. To this effect, we will use a unique strain of Apc+/Min mice as a model of sporadic colorectal cancer. Therefore, the hypothesis that we want to test is that STAT2 is a molecular target in the chemoprevention of colorectal cancer. To test our hypothesis, we propose the following Specific Aim: Determine the contribution of STAT2 in the progression of colorectal cancer in Apc+/Min mice. In this Aim we will:(1) Generate Apc+/Min STAT2-/- mice, (2) Determine whether STAT2 in the Apc+/Min mouse affects survival and (3) Determine whether STAT2 affects colorectal tumor progression in the Apc+/Min mouse. Significance: These results will provide insights into whether STAT2 is oncogenic and may serve as a biomarker and/or molecular target for the chemoprevention of colorectal cancer.
STAT2 belongs to a family of transcription factors that induce the expression of many genes;which among them play roles in controlling viral infection and tumor cell growth. Our recent findings indicate that STAT2 contributes to tumor development in carcinogen-induced animal models of colon and skin cancer. This makes STAT2 an attractive molecular target for cancer prevention. The goal of our project is to validate the tumor promoting activities of STAT2 using a spontaneous animal model of colorectal cancer.