The Role of A20 in Colitis-Associated Cancer

A20 在结肠炎相关癌症中的作用

• 批准号: 9901520
• 负责人: Ling Shao
• 金额: $ 12.38万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901520
• 关键词: Affect; Animals; Attention; Autoimmune Diseases; Autoimmune Process; Azoxymethane; B-Lymphocytes; Blood; Cell Death; Cell Line; Cells; Characteristics; Chronic; Clinical; Colitis; Colitis associated colorectal cancer; Colon; Colon Carcinoma; Colorectal; Colorectal Adenoma; Colorectal Cancer; Cytokine Gene; DNA Damage; DNA Sequence Alteration; Data; Development; Dextrans; Diarrhea; Disease; Dose; Enzymes; Epithelial; Epithelial Cells; Epithelium; Exposure to; Feces; Functional disorder; Gene Expression; Gene Expression Profile; Gene Targeting; General Population; Genes; Genetic Transcription; Goals; Histology; Human; Hyperactive behavior; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-1; Intestines; Investigation; Irritants; Knock-out; Knockout Mice; Knowledge; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Molecular Profiling; Mus; Mutagens; Neoplasms; Oncogenic; Organoids; Pathogenesis; Pathway interactions; Patients; Play; Production; Proliferation Marker; Proteins; Regulation; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Small Intestines; Sodium Dextran Sulfate; Somatic Mutation; System; TNF gene; Testing; Tissues; Tumor Burden; Tumor Suppressor Proteins; Tumor stage; Ubiquitin; Weight; Wild Type Mouse; Work; autoinflammatory; base; beta catenin; cancer type; carcinogenesis; carcinogenicity; chronic inflammatory disease; colitis associated cancer; colorectal cancer risk; cytokine; early onset; genetic signature; genome wide association study; in vivo; inhibitor/antagonist; intestinal epithelium; loss of function mutation; mouse model; new therapeutic target; sodium sulfate; transcriptome sequencing; trend; tumor

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.

项目摘要 自古以来，慢性炎症就与恶性肿瘤的发展有关。比如说， 炎症性肠病（IBD）患者，一种肠道慢性炎症性疾病，表现为 与普通人群相比，他们一生中患结肠直肠癌的风险增加了六倍。 重要的是，这些结肠炎相关癌症的发病机制知之甚少，但似乎是不同的 散发性结直肠癌的发病率。TNF-α诱导蛋白3（TNFAIP 3）， 也称为A20，是一种泛素编辑酶，是一种众所周知的炎症抑制剂，特别是 TNF-α信号的下游。全基因组关联研究已将A20与多种 炎症和自身免疫性疾病，如IBD。缺乏A20的小鼠迅速发展致命的严重 包括结肠在内的多个组织的全身性炎症。同样，患有罕见功能丧失的患者 A20突变发展为早发性自身炎性疾病。除了在炎症中有明确的作用外， 在多种类型的癌症中发现了A20的体细胞突变，这表明这种蛋白质也 作为肿瘤抑制因子。事实上，我们以前的工作表明，A20可能在以下方面发挥直接作用： 调节Wnt/β-连环蛋白信号传导。已知该途径在以下疾病的发病机制中至关重要： 散发性结肠癌基于这些数据，我们假设A20可能是一个重要的调节因子， 炎症相关的癌症，特别是结肠癌。在本申请中，我们建议研究 在结肠炎相关癌症的经典小鼠模型中，结肠上皮细胞特异性A20缺陷。在 在该系统中，小鼠注射单剂量的遗传毒素氧化偶氮甲烷（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， 肠上皮细胞特异性A20缺失将产生比野生型更大和更多的肿瘤 暴露于AOM-DSS的小鼠。我们进一步建议使用细胞系在体外检查基因表达的变化 以及在用促炎和促癌物质刺激后A20缺乏的鼠肠类器官 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 结肠炎相关的癌症，并可能为这种独特的临床实体提供新的治疗靶点。

项目成果

A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer.

• DOI: 10.1016/j.gastha.2022.09.004
• 发表时间: 2023
• 期刊: Gastro hep advances
• 作者: Basta, David W;Vong, Mandy;Beshimova, Adolat;Nakamura, Brooke N;Rusu, Iulia;Kattah, Michael G;Shao, Ling
• 通讯作者: Shao, Ling