Evaluation of STAT2 in a Model of Sporadic Colorectal Cancer

散发性结直肠癌模型中 STAT2 的评估

• 批准号: 8322638
• 负责人: ANA M GAMERO
• 金额: $ 7.65万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322638
• 关键词: Affect; Age; Anemia; Animal Cancer Model; Animal Model; Apoptotic; Appearance; Applications Grants; Azoxymethane; Biological Markers; Body Weight decreased; Carcinogens; Cell Death Inhibition; Chemoprevention; Chronic; Colitis; Colon; Colon Carcinoma; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Development; Disease; Evaluation; Family; Female; Fox Chase Cancer Center; Funding; Generations; Genes; Genetic; Goals; Hemorrhage; Human Development; Incidence; Inflammation; Inflammatory; Interferon Type I; Interferons; Interleukin-6; Intestinal Neoplasms; Lesion; Link; Loss of Heterozygosity; Malignant Neoplasms; Mediating; Modeling; Molecular Target; Monitor; Mus; NIH Program Announcements; Oncogenic; Organ; Play; Prevention Research; Publishing; Rectal Prolapse; Reporting; Research Project Grants; Resistance; Role; STAT2 gene; STAT3 gene; Skin Cancer; Small Intestines; Sodium Dextran Sulfate; Staging; Testing; Tumor Promoters; Tumor Suppressor Proteins; Virus Diseases; Wild Type Mouse; adenoma; base; cancer prevention; carcinogenesis; cell growth; colitis associated cancer; colon carcinogenesis; combinatorial; cytokine; insight; male; member; mouse model; neoplastic cell; offspring; programs; rectal; response; transcription factor; tumor; tumor progression; tumorigenesis

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.

说明（由申请人提供）：此 R03 癌症预防研究拨款申请是根据计划公告 (PA) 编号：PAR-08-055 提交的。正在申请资金来验证转录因子 STAT2 在结直肠肿瘤发生中的作用。我们的方法是使用 Fox Chase 癌症中心培育的独特的多发性肠肿瘤 (Apc+/Min) 小鼠品系。这些小鼠自发地产生大量结直肠腺瘤；因此，它们是研究 STAT2 对结直肠肿瘤发生影响的合适动物模型。虽然人们普遍认为 STAT 家族的其他成员在人类癌症的发展中发挥着积极作用，但目前尚不清楚 STAT2 在肿瘤发生中的确切功能是什么。 STAT2 是一种转录因子，已知可介导 I 型干扰素的抗增殖和细胞凋亡作用，因此表明 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 在促进结直肠癌发生中是必需的。在结肠炎相关癌症的小鼠模型中，与野生型小鼠相比，我们发现 STAT2-/- 小鼠对氧化偶氮甲烷和葡聚糖硫酸钠的组合致癌作用具有更强的抵抗力。 STAT2-/-小鼠的存活时间更长，腺瘤更少，病变尺寸更小；所有这些都表明肿瘤进展延迟。此外，STAT2 增强了 STAT3 的激活和促炎性 IL-6 的分泌，IL-6 是一种多功能细胞因子，最近报道是早期结肠炎相关肿瘤发生过程中的关键肿瘤促进剂。因此，我们的研究发现 STAT2 作为结直肠癌化学预防的潜在分子靶点。本次拨款申请的目的是在不同的结直肠癌动物模型中验证 STAT2 的肿瘤促进作用。为此，我们将使用独特的 Apc+/Min 小鼠品系作为散发性结直肠癌模型。因此，我们要检验的假设是STAT2是结直肠癌化学预防的分子靶点。 为了检验我们的假设，我们提出以下具体目标：确定 STAT2 在 Apc+/Min 小鼠结直肠癌进展中的贡献。在此目标中，我们将：(1) 生成 Apc+/Min STAT2-/- 小鼠，(2) 确定 Apc+/Min 小鼠中的 STAT2 是否影响生存，以及 (3) 确定 STAT2 是否影响 Apc+/Min 小鼠中的结直肠肿瘤进展。 意义：这些结果将深入了解 STAT2 是否具有致癌性，并可作为结直肠癌化学预防的生物标志物和/或分子靶点。