The Role of STAT2 in Flat Non-Polypoid Colorectal Neoplasia

摘要 非息肉样(扁平)结直肠肿瘤占所有结直肠病变的三分之二 在炎症性肠病(IBD)患者中， 结直肠癌，即结肠炎相关性结肠癌(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三倍 因为它们更难被发现和完全移除。因此，识别分子 负责确定肿瘤是扁平的还是息肉样变的通路可能提供 对癌症预防和/或治疗的有价值的见解。此前的研究表明，这一时机 在结直肠癌的发展过程中，P53的改变决定了肿瘤是扁平的还是 我们最近的研究表明转录因子STAT2可能是一种必需的 分子在扁平结直肠腺瘤发生发展中的作用。因此，我们建议测试 STAT2促进扁平非息肉体AS优先发展的假说 与P53失活后的息肉状结直肠肿瘤相反。我们计划解决这个问题 通过执行以下中心目标：确定STAT2在Flat开发中的作用 非息肉样结直肠肿瘤中P53失活处理的两个重要问题 问题：1)结肠上皮细胞固有的STAT2信号在结肠炎的形成中起作用吗？ 扁平非息肉样肿瘤？2)STAT2是否激活并维持促炎作用？ 有利于扁平非息肉体结直肠癌优先发展的微环境 当P53在结肠上皮中失活时会发生肿瘤吗？为了研究STAT2在血管紧张素转换酶中的作用 对于扁平非息肉样病变的发展，我们将使用成熟的硫酸葡聚糖 应用条件性P53和Stat2基因敲除小鼠建立钠(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：我们的发现将提供有关细胞初始转化的关键信息 导致扁平非息肉状结直肠肿瘤的事件，这些肿瘤更有可能成为 P53失活条件下的癌症；我们仍了解的一个主要知识缺口 很少。因此，明确STAT2在扁平结肠肿瘤发展中的作用是关键。 肿瘤生物标志物的鉴定作为预测癌症预防和发展的工具 新的靶向治疗。

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.