Mechanisms Underlying Colorectal Cancer Risk in IBD (PQ6)

描述（由申请人提供）：已知癌症是由影响细胞生长、基因组稳定性并允许持续自我更新的非致死性突变和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率，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。该应用旨在确定IBD患者增加结直肠癌风险的分子和细胞机制，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的胞苷脱氨酶（AID）的表达是由结肠炎症诱导的，并且AID表达可以增强结肠上皮细胞对p53突变的获得。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“干性”（自我更新特性），我们假设结肠上皮细胞内AID表达的诱导引起“完美风暴”，其可以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。在本研究中，我们将确定诱导AID的能力如何影响IBD新型小鼠模型中结直肠肿瘤的发生率，该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。将在肿瘤性病变和邻近外观正常的粘膜中评估已知是结直肠肿瘤形成关键驱动因素的基因和途径的突变和/或失调的获得，作为结肠炎持续时间的函数。结果将增强我们对与炎症相关结直肠癌的发展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，这些生物标志物将允许早期和/或非侵入性诊断方法，并将为开发药物以降低炎症相关和散发性结直肠癌的风险奠定基础。 公共卫生相关性：结直肠癌是美国最常见的癌症。患有炎症性肠病（IBD）的患者经历慢性结肠炎症，这使他们的结肠癌风险比一般人群高出20倍。因此，开发安全有效的策略来减少炎症相关结肠癌的发展将对IBD患者特别有益，但由于炎症也可能在散发性结肠癌的发展中发挥作用，因此也将使其他人群受益。

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. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the 3d most common cancer in the United States. Patients with inflammatory bowel disease (IBD) experience chronic colon inflammation that increases their colon cancer risk by as much as 20-fold above that of the general population. Development of safe and effective strategies to decrease the development of inflammation-associated colon cancer would thus be of particular benefit to IBD patients but, since inflammation may also play a role in the development of sporadic colon cancers, would benefit the rest of population as well.