Mechanisms Underlying Colorectal Cancer Risk in IBD (PQ6)

描述（由申请人提供）：已知癌症是由非致死突变和影响细胞生长、基因组稳定性并允许持续自我更新的基因调控变化的积累引起的。虽然结肠内炎症产生的氧化应激可以明显提高突变积累的速度，但仅凭这一点似乎不足以解释炎症性肠病（IBD）患者患结直肠癌的极高风险。该应用程序旨在确定IBD患者发生结直肠癌风险增加的分子和细胞机制，并探索如何利用这些联系来开发新的预防或治疗策略（NCI的挑衅性问题6）。最近的研究表明，突变诱导酶激活诱导胞苷脱氨酶（AID）的表达可被结肠炎症诱导，AID的表达可增强结肠上皮细胞对p53突变的获取。基于最近的数据表明AID也可以通过其对基因甲基化的影响来影响“干细胞性”（自我更新特性），我们假设在结肠上皮细胞中诱导AID表达会导致“完美风暴”，通过同时增加突变率、降低基因组稳定性和赋予作为癌症标志的自我更新特性而迅速导致结肠癌的发展。在这项研究中，我们将确定在一种新的IBD小鼠模型中，诱导AID的能力如何影响结直肠肿瘤的发生率，这种模型在临床表现和癌症易感性方面与人类溃疡性结肠炎非常相似。在肿瘤病变和相邻正常粘膜中，作为结肠炎持续时间的函数，将评估作为结直肠瘤变关键驱动因素的基因和通路的获得性突变和/或失调。结果将增强我们对与炎症相关结直肠癌发生和进展相关的分子信号通路的理解。重要的是，他们将确定关键的生物标志物，这将允许早期和/或非侵入性诊断方法，并将为开发降低炎症相关和散发性结直肠癌风险的药物奠定基础。

DESCRIPTION (provided by applicant): Cancer is known to result from accumulation of non-lethal mutations and changes in gene regulation that affect cell growth, genomic stability, and allow continuous self-renewal. Although the oxidative stress generated by inflammation within the colon can clearly enhance the rate of mutation accumulation, this alone appears to be insufficient to explain the extremely high risk of colorectal cancer in patients with inflammatory bowel disease (IBD). This application is designed to determine the molecular and cellular mechanisms by which patients with IBD has increased risk for developing colorectal cancer and to explore how these connections can be exploited to develop novel preventive or therapeutic strategies (NCI's provocative question 6). Recent research has shown that the expression of the mutation-inducing enzyme activation-induced cytidine deaminase (AID) is induced by colon inflammation and that AID expression can enhance the acquisition of p53 mutations by colon epithelial cells. Based on very recent data indicating that AID can also affect "stemness" (self-renewal properties) via its effects on gene methylation, we hypothesize that induction of AID expression within colon epithelial cells causes a "perfect storm" that can rapidly lead to development of colon cancer by simultaneously increasing mutation rates, decreasing genome stability, and conferring the self-renewal properties that are a hallmark of cancer. For this study we will determine how the ability to induce AID affects the incidence of colorectal neoplasia in a novel murine model of IBD that very closely resembles human ulcerative colitis in both clinical presentation and cancer susceptibility. Acquisition of mutations and/or dysregulation in genes and pathways that are known to be critical drivers of colorectal neoplasia will be assessed in both neoplastic lesions and adjacent normal-appearing mucosa as a function of colitis duration. Results will enhance our understanding of molecular signaling pathways that are relevant to the development and progression of inflammation-associated colorectal cancer. Importantly, they will identify critical biomarkers that will allow earlier and/or non-invasive methods of diagnosis and will lay the foundation for development of drugs to decrease risk of inflammation-associated and sporadic colorectal cancers.