The Role of STAT2 in Flat Non-Polypoid Colorectal Neoplasia

STAT2 在扁平非息肉样结直肠肿瘤中的作用

• 批准号: 9305364
• 负责人: ANA M GAMERO
• 金额: $ 7.8万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305364
• 关键词: Address; Adenomatous Polyps; Alpha Cell; Anatomy; Animal Model; Animals; Applications Grants; Azoxymethane; Biological Assay; CDX2 gene; Carcinoma; Chemical Models; Co-Immunoprecipitations; Colitis; Colon; Colon Carcinoma; Colonic Neoplasms; Colonoscopy; Colorectal; Colorectal Adenocarcinoma; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Crohn' s disease; Decision Making; Development; Disease; Epithelial Cells; Epithelium; Event; Frequencies; Genetic; Genotype; Human; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Invaded; Knockout Mice; Knowledge; Lesion; Light; LoxP-flanked allele; Malignant Neoplasms; Modeling; Molecular; Monitor; Morphology; Mus; Oncogenic; Pathway interactions; Patients; Periodicity; Play; Polypoid Lesion; Positioning Attribute; Process; Property; Proteins; Risk; Risk Factors; Role; STAT2 gene; Severities; Signal Transduction; Sodium Dextran Sulfate; TP53 gene; Testing; Therapeutic Intervention; Time; Tumor Cell Line; Tumor Markers; Tumorigenicity; Ulcerative Colitis; United States; Wild Type Mouse; adenoma; attenuation; cancer cell; cancer prevention; colitis associated cancer; colon carcinogenesis; combinatorial; high risk; illness length; inflammatory marker; insight; knock-down; metaplastic cell transformation; mouse model; new therapeutic target; predictive tools; response; sex; transcription factor; tumor; tumorigenic

Summary Non-polypoid (flat) colorectal neoplasms account for as many as two-thirds of all colorectal lesions in patients with inflammatory bowel disease (IBD), a high risk factor for the development of colorectal cancer (CRC), namely, colitis-associated colon cancer (CAC). Flat lesions are five times more likely than polypoid lesions to progress to invasive colorectal adenocarcinoma, in part because they are more difficult to detect and completely remove. Thus, identifying the molecular pathways responsible for determining whether tumors become flat or polypoid may provide valuable insight into cancer prevention and/or treatment. Previous studies suggest that the timing of p53 alterations in colorectal cancer development determine whether the tumors are flat or polypoid, and our recent studies suggest that the transcription factor STAT2 may be an essential molecule in the development of flat colorectal adenomas. Thus, we propose to test the hypothesis that STAT2 contributes to the preferential development of flat non-polypoid as opposed to polypoid colorectal tumors following p53 inactivation. We plan to address this by performing the following central aim: Determine the role of STAT2 in the development of flat non-polypoid colorectal tumors in the setting of p53 inactivation to address two important questions: 1) does colonic epithelial cell intrinsic STAT2 signaling play a role in the formation of flat non-polypoid tumors?, and 2) does STAT2 activate and sustain a pro-inflammatory microenvironment conducive to the preferential development of flat non-polypoid colorectal tumors when p53 is inactivated in the colonic epithelium? To investigate the effect of STAT2 in the development of flat non-polypoid lesions, we will employ the well-established dextran sulfate sodium (DSS)-induced colitis model using conditional p53 and Stat2 knockout mice and conventional Stat2 knockout mice. With this model, we are in a unique position to monitor disease development and progression. Significance: Our findings will provide crucial information on the initial cellular transformation events that give rise to flat non-polypoid colorectal tumors, which are more likely to become cancer under conditions of p53 inactivation; a major gap in knowledge to which we still understand very little. Hence defining the role of STAT2 in the development of flat colonic tumors is key in the identification of tumor biomarkers as predictive tools for cancer prevention and development of novel targeted therapies.

概括 非息肉样（扁平）结直肠肿瘤占所有结直肠病变的三分之二 炎症性肠病 (IBD) 患者是发生炎症性肠病的高危因素 结直肠癌（CRC），即结肠炎相关结肠癌（CAC）。扁平病变有五个 部分进展为侵袭性结直肠腺癌的可能性是息肉样病变的数倍 因为它们更难以检测和完全删除。因此，识别分子 负责确定肿瘤是否变得扁平或息肉状的途径可能提供 对癌症预防和/或治疗的宝贵见解。先前的研究表明，时机 结直肠癌发展过程中 p53 的改变决定了肿瘤是扁平的还是扁平的 息肉状细胞，我们最近的研究表明转录因子 STAT2 可能是一个重要的 扁平结直肠腺瘤发展中的分子。因此，我们建议测试 假设 STAT2 有助于扁平非息肉体的优先发育 与 p53 失活后的息肉样结直肠肿瘤相反。我们计划解决这个问题 通过执行以下中心目标： 确定 STAT2 在扁平化发展中的作用 p53 失活背景下的非息肉样结直肠肿瘤解决两个重要问题 问题：1）结肠上皮细胞内在的STAT2信号传导在结肠上皮细胞的形成中发挥作用吗？ 扁平非息肉样肿瘤？，2) STAT2 是否激活并维持促炎性 有利于扁平非息肉状结直肠优先发育的微环境 当p53在结肠上皮中失活时会产生肿瘤吗？研究 STAT2 在 扁平非息肉样病变的发展，我们将使用成熟的硫酸葡聚糖 使用条件性 p53 和 Stat2 基因敲除小鼠的钠 (DSS) 诱导的结肠炎模型 传统的 Stat2 基因敲除小鼠。有了这个模型，我们在监测疾病方面处于独特的地位 发展和进步。 意义：我们的研究结果将提供有关初始细胞转化的重要信息 引起扁平非息肉样结直肠肿瘤的事件，这些肿瘤更有可能变成 p53 失活条件下的癌症；我们仍然了解的知识上的重大差距 很少。因此，确定 STAT2 在扁平结肠肿瘤发展中的作用是研究的关键。 识别肿瘤生物标志物作为癌症预防和发展的预测工具 新颖的靶向疗法。