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: 8203847
• 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/8203847
• 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. 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.

描述（由申请人提供）：此R03癌症预防研究赠款申请正在响应计划公告（PA）编号：PAR-08-055。要求资金验证转录因子STAT2在结直肠肿瘤发生中的贡献。我们的方法是使用在Fox Chase癌症中心产生的多种肠道肿瘤（APC+/min）小鼠的独特菌株。这些小鼠会自发地形成大量的结直肠腺瘤和；因此，是研究STAT2对结直肠肿瘤发生的影响的合适动物模型。尽管人们认为，STAT家族的其他成员在人类癌症的发展中起着积极作用，但尚不清楚STAT2在肿瘤发生中的确切功能是什么。 STAT2是一种转录因子，用于介导I型干扰素的抗增生性和凋亡作用，因此表明STAT2可以作为肿瘤抑制器起作用。但是，我们最近的研究的结果与这种观点相矛盾，因为我们发现在促进结直肠癌发生时STAT2是必需的。与野生型小鼠相比，在与结肠炎相关的癌症的小鼠模型中，我们发现STAT2 - / - 小鼠对甲氧基烷和硫酸葡萄糖钠的联合性致癌作用具有更耐药性。 STAT2 - / - 小鼠的生存率延长，腺瘤较少，病变的大小较小。所有这些都表示肿瘤进展的延迟。此外，STAT2增强了促炎性IL-6的STAT3激活和分泌，这是一种多功能细胞因子，最近据报道是早期结肠炎相关的肿瘤发生期间是关键的肿瘤启动子。因此，我们的研究将STAT2视为结直肠癌化学预防的潜在分子靶标。该赠款应用的目的是验证在大肠癌的不同动物模型中促进STAT2的肿瘤促进作用。为此，我们将使用独特的APC+/min小鼠菌株作为零星结直肠癌的模型。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标。 为了检验我们的假设，我们提出了以下特定目的：确定STAT2在APC+/min小鼠中结直肠癌进展中的贡献。在此目的中，我们将：（1）生成APC+/min Stat2 - / - 小鼠，（2）确定APC+/min小鼠中的STAT2是否会影响生存，（3）确定STAT2是否影响APC+/min Mouse中的结直肠肿瘤进展。 意义：这些结果将提供有关STAT2是否具有致癌性的见解，并且可以作为结直肠癌化学预防的生物标志物和/或分子靶标。 公共卫生相关性：STAT2属于诱导许多基因表达的转录因子家族。其中其中在控制病毒感染和肿瘤细胞生长中起着作用。我们最近的发现表明，STAT2有助于致癌的结肠和皮肤癌动物模型的肿瘤发展。这使STAT2成为预防癌症的有吸引力的分子靶标。我们项目的目的是使用自发的大肠癌动物模型来验证STAT2的肿瘤促进活性。