Evaluation of STAT2 in a Model of Sporadic Colorectal Cancer

描述（由申请人提供）：根据项目公告（PA）编号：PAR-08-055，现提交R03癌症预防研究资助申请。正在申请资金以验证转录因子STAT2在结直肠肿瘤发生中的作用。我们的方法是使用Fox Chase癌症中心产生的一种独特的多发性肠肿瘤（Apc+/Min）小鼠。这些小鼠自发产生大量的结直肠腺瘤和；因此，是研究STAT2对结直肠肿瘤发生影响的合适动物模型。虽然STAT家族的其他成员在人类癌症的发展中发挥积极作用是公认的，但STAT2在肿瘤发生中的确切功能尚不清楚。STAT2是一种已知的转录因子，可介导I型干扰素的抗增殖和凋亡作用，因此表明STAT2可能作为肿瘤抑制因子起作用。然而，我们最近的研究结果与这一观点相矛盾，因为我们发现STAT2在促进结直肠癌发生中是必需的。在结肠炎相关癌症小鼠模型中，与野生型小鼠相比，我们发现STAT2-/-小鼠对偶氮氧甲烷和葡聚糖硫酸钠的联合致癌作用更具抵抗力。STAT2-/-小鼠存活时间延长，腺瘤发生较少，病变大小较小；这些都表明肿瘤进展有所延缓。此外，STAT2增强STAT3的激活和促炎IL-6的分泌，IL-6是一种多功能细胞因子，最近被报道为早期结肠炎相关肿瘤发生过程中的关键肿瘤启动子。因此，我们的研究揭示了STAT2作为结直肠癌化学预防的潜在分子靶点。本拨款申请的目的是验证STAT2在不同的结直肠癌动物模型中的促肿瘤作用。为此，我们将使用一种独特的Apc+/Min小鼠菌株作为散发性结直肠癌的模型。因此，我们想要验证的假设是STAT2是化学预防结直肠癌的分子靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.