Evaluation of STAT2 in a Model of Sporadic Colorectal Cancer
散发性结直肠癌模型中 STAT2 的评估
基本信息
- 批准号:8322638
- 负责人:
- 金额:$ 7.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAgeAnemiaAnimal Cancer ModelAnimal ModelApoptoticAppearanceApplications GrantsAzoxymethaneBiological MarkersBody Weight decreasedCarcinogensCell Death InhibitionChemopreventionChronicColitisColonColon CarcinomaColorectalColorectal AdenomaColorectal CancerColorectal NeoplasmsDevelopmentDiseaseEvaluationFamilyFemaleFox Chase Cancer CenterFundingGenerationsGenesGeneticGoalsHemorrhageHuman DevelopmentIncidenceInflammationInflammatoryInterferon Type IInterferonsInterleukin-6Intestinal NeoplasmsLesionLinkLoss of HeterozygosityMalignant NeoplasmsMediatingModelingMolecular TargetMonitorMusNIH Program AnnouncementsOncogenicOrganPlayPrevention ResearchPublishingRectal ProlapseReportingResearch Project GrantsResistanceRoleSTAT2 geneSTAT3 geneSkin CancerSmall IntestinesSodium Dextran SulfateStagingTestingTumor PromotersTumor Suppressor ProteinsVirus DiseasesWild Type Mouseadenomabasecancer preventioncarcinogenesiscell growthcolitis associated cancercolon carcinogenesiscombinatorialcytokineinsightmalemembermouse modelneoplastic celloffspringprogramsrectalresponsetranscription factortumortumor progressiontumorigenesis
项目摘要
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.
描述(由申请人提供):此R 03癌症预防研究补助金申请正在提交,以响应计划公告(PA)编号:PAR-08-055。正在申请资金以验证转录因子STAT 2在结直肠肿瘤发生中的作用。我们的方法是使用在Fox Chase癌症中心产生的多发性肠肿瘤(Apc+/Min)小鼠的独特品系。这些小鼠自发地产生大量的结直肠腺瘤,因此,是研究STAT 2对结直肠肿瘤发生的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起着积极的作用,但STAT 2在肿瘤发生中的确切功能仍不清楚。STAT 2是一种转录因子,已知其介导I型干扰素的抗增殖和凋亡作用,因此表明STAT 2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STAT 2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STAT 2-/-小鼠对氧化偶氮甲烷和葡聚糖硫酸钠的组合致癌作用更具抗性。 STAT 2-/-小鼠表现出延长的存活期,发展出较少的腺瘤,病变的大小较小;所有这些都表明肿瘤进展延迟。此外,STAT 2增强STAT 3激活和促炎性IL-6的分泌,促炎性IL-6是一种多功能细胞因子,最近报道在早期结肠炎相关肿瘤发生期间是关键的肿瘤促进剂。因此,我们的研究发现STAT 2是结直肠癌化学预防的潜在分子靶点。这项资助申请的目的是验证STAT 2在结直肠癌的不同动物模型中的肿瘤促进作用。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模型。因此,我们想要验证的假设是STAT 2是结直肠癌化学预防中的分子靶点。
为了检验我们的假设,我们提出了以下具体目标:确定STAT 2在Apc+/Min小鼠中结肠直肠癌进展中的作用。在此目的中,我们将:(1)产生Apc+/Min STAT 2-/-小鼠,(2)确定在Apc+/Min小鼠中STAT 2是否影响存活,以及(3)确定在Apc+/Min小鼠中STAT 2是否影响结肠直肠肿瘤进展。
重要性:这些结果将为STAT 2是否致癌提供见解,并可能作为结直肠癌化学预防的生物标志物和/或分子靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ANA M GAMERO其他文献
ANA M GAMERO的其他文献
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{{ truncateString('ANA M GAMERO', 18)}}的其他基金
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8253486 - 财政年份:2009
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