Evaluation of STAT2 in a Model of Sporadic Colorectal Cancer

描述(由申请人提供)：本R03癌症预防研究资助申请是根据计划公告(PA)提交的，编号：PAR-08-055。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。我们的方法是使用福克斯·蔡斯癌症中心培育的一种独特的多发性肠道肿瘤(APC+/Min)小鼠。这些小鼠自发形成大量的结直肠腺瘤，因此，是研究STAT2对结直肠癌发生的影响的合适的动物模型。虽然STAT家族的其他成员在人类癌症的发展中发挥了积极的作用，但目前还不清楚STAT2在肿瘤发生中的确切作用。STAT2是一种转录因子，以介导I型干扰素的抗增殖和凋亡作用而闻名，因此提示STAT2可能作为肿瘤抑制因子发挥作用。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在促进结直肠癌的发生中是必需的。在结肠炎相关癌症的小鼠模型中，我们发现与野生型小鼠相比，STAT2-/-小鼠对偶氮甲烷和葡聚糖硫酸钠的联合致癌作用更具抵抗力。STAT2-/-小鼠的存活时间延长，发生的腺瘤较少，病变较小；所有这些都表明肿瘤进展缓慢。此外，STAT2促进STAT3的激活和促炎IL-6的分泌，IL-6是一种多功能细胞因子，最近被报道在结肠炎相关的早期肿瘤发生中是一个关键的肿瘤促进剂。因此，我们的研究发现STAT2是结直肠癌化学预防的潜在分子靶点。这项拨款申请的目的是验证STAT2在一种不同的结直肠癌动物模型中的促癌作用。为此，我们将使用一种独特的APC+/Min小鼠品系作为散发性结直肠癌的模型。因此，我们想要检验的假设是，STAT2是结直肠癌化学预防的分子靶点。 为了验证我们的假设，我们提出了以下具体目标：确定STAT2在APC+/Min小鼠结直肠癌进展中的作用。为此，我们将：(1)建立APC+/Min STAT2-/-小鼠，(2)确定APC+/Min小鼠中的STAT2是否影响生存，(3)确定STAT2是否影响APC+/Min小鼠的结直肠癌进展。 意义：这些结果将提供关于STAT2是否致癌的见解，并可能作为结直肠癌化学预防的生物标记物和/或分子靶点。

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.