The Role of A20 in Colitis-Associated Cancer

项目摘要 自古以来，慢性炎症与恶性肿瘤的发生发展密切相关。例如, 炎症性肠病(IBD)是一种慢性肠道炎症性疾病，患者表现为 与普通人群相比，他们一生中患结直肠癌的风险增加了6倍。 重要的是，这些结肠炎相关癌症的发病机制尚不清楚，但似乎是截然不同的。 由普通人群中发生的散发性结直肠癌引起。肿瘤坏死因子-α诱导蛋白3(TNFAIP3)， 也被称为A20，是一种泛素编辑酶，是一种众所周知的炎症抑制剂，尤其是 在肿瘤坏死因子-α信号的下游。全基因组关联研究强烈地将A20与多个 炎症性和自身免疫性疾病，如IBD。缺乏A20的小鼠迅速发展为致命的严重 包括结肠在内的多种组织的全身性炎症。同样，患有罕见功能丧失的患者 A20基因突变会发展为早发性自身炎症性疾病。除了在炎症中起到明确的作用 疾病，A20的体细胞突变在多种类型的癌症中被发现，这表明该蛋白也 作为一种肿瘤抑制因子。事实上，我们之前的工作表明，A20可能在 调节WNT/β-连环蛋白信号。已知这一途径在糖尿病的发病机制中起着至关重要的作用。 散发性结肠癌。根据这些数据，我们推测A20可能是一个重要的调节因子。 炎症与癌症相关，尤其是在结肠。在这一应用中，我们建议研究 在结肠炎相关癌症的经典小鼠模型中，A20的肠道上皮细胞特异性缺陷的研究。在……里面 在这个系统中，小鼠被单次注射一种基因毒素--偶氮甲烷(AOM)，然后重复 使用上皮刺激物葡聚糖硫酸钠(DSS)诱导结肠炎。我们假设老鼠身上有 肠上皮细胞特异性缺失A20会比野生型发生更大更多的肿瘤 AOM-DSS染毒小鼠。我们进一步建议使用细胞系在体外检测基因表达的变化。 以及在促炎和致癌刺激后缺乏A20的小鼠肠道有机物质 细胞因子。这些研究将有助于阐明A20影响的特定转录网络和途径 在这种情况下的破坏。我们的最终目标是更好地了解糖尿病的潜在病理生理学 结肠炎相关癌症，并有可能为这一独特的临床实体提供新的治疗靶点。

Project Summary Chronic inflammation has been associated with the development of malignancy since antiquity. For example, patients with inflammatory bowel disease (IBD), a chronic inflammatory disease of the intestines, manifest as much as a six-fold increased risk of colorectal cancer over their lifetime compared to the general population. Importantly, the pathogenesis of these colitis-associated cancers is poorly understood, but appears to be distinct from sporadic colorectal cancers that occur in the general population. TNF-alpha induced protein 3 (TNFAIP3), also known as A20, is a ubiquitin editing enzyme that is a well-known inhibitor of inflammation, particularly downstream of TNF-alpha signaling. Genome-wide association studies have strongly linked A20 to multiple inflammatory and autoimmune diseases such as IBD. Mice deficient in A20 develop rapidly lethal severe systemic inflammation in multiple tissues including the colon. Similarly, patients with a rare loss-of-function mutation in A20 develop early-onset autoinflammatory disease. In addition to a clear role in inflammatory disease, somatic mutations in A20 have been found in multiple types of cancer suggesting this protein also serves as a tumor suppressor. Indeed, our previous work demonstrated that A20 might play a direct role in regulating wnt/beta-catenin signaling. This pathway is known to be critically important in the pathogenesis of sporadic colon cancers. Based on these data, we hypothesize that A20 may be an important regulator of inflammation associated cancers particularly in the colon. In this application, we propose to study the effect of intestinal-epithelial cell specific deficiency of A20 in a classical murine model of colitis-associated cancer. In this system, mice are injected with a single dose of a genotoxin, azoxymethane (AOM), followed repeated induction of colitis using an epithelial irritant, dextran sodium sulfate (DSS). We hypothesize that mice with intestinal epithelial cell-specific deletion of A20 will develop larger and more numerous tumors than wild-type mice exposed to AOM-DSS. We further propose to examine gene expression changes in vitro using cell lines and murine intestinal organoids deficient in A20 after stimulation with pro-inflammatory and pro-carcinogenic cytokines. These studies will help elucidate the specific transcriptional networks and pathways affected by A20 disruption under these conditions. Our ultimate goal is to better understand the underlying pathophysiology of colitis-associated cancers and potentially provide novel therapeutic targets for this distinct clinical entity.