Inflammation and Cancer

炎症和癌症

• 批准号: 7291773
• 负责人: CURTIS HARRIS
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7291773
• 关键词: Inflammation; Cancer

Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Chronic inflammation can increase cancer risk. We are investigating the interaction between nitric oxide (NO∙) and p53 as a crucial pathway in inflammatory-mediated carcinogenesis. We have shown that NO∙ induces ATM- and ATR-dependent p53 posttranslational modifications leading to a p53 stress response in human cells in vitro, in an admixture of activated macrophages and human cells in vitro, and in colon tissue from patients with ulcerative colitis, a cancer prone, chronic inflammatory disease. We also discovered a novel mechanism of microsatellite instability caused by an adaptative imbalance in base excision repair enzymes in these patients. Chronic inflammation can also increase p53 mutation load in ulcerative colitis. In addition, we are comparing the role of inflammation in colon carcinogenesis in ulcerative colitis versus Crohn's disease. Animal models are a critical facet of our integrative biology strategy, hence we have utilized genetic knockouts, e.g., p53 and inducible nitric oxide synthase, to investigate mechanisms of inflammation-associated cancer. Modest increases in NO∙ cause growth arrest and apoptosis to delay tumor formation, whereas higher NO∙ amounts are associated with inflammation and increased tumor formation. We will also explore the hypothesis that the increased cancer risk with obesity is related to a proinflammatory state.

自由基在我们体内无处不在，是由正常的生理过程产生的，包括有氧代谢和炎症反应，以消除入侵的病原微生物。慢性炎症会增加癌症风险。我们正在研究一氧化氮 (NO∙) 和 p53 之间的相互作用，作为炎症介导的致癌作用的关键途径。我们已经证明，NO∙ 诱导 ATM 和 ATR 依赖性 p53 翻译后修饰，导致体外人体细胞、体外活化的巨噬细胞和人体细胞的混合物以及溃疡性结肠炎（一种易患癌症的慢性炎症性疾病）患者的结肠组织中的 p53 应激反应。我们还发现了由这些患者碱基切除修复酶的适应性失衡引起的微卫星不稳定的新机制。慢性炎症也会增加溃疡性结肠炎的 p53 突变负荷。此外，我们正在比较炎症在溃疡性结肠炎和克罗恩病的结肠癌发生中的作用。动物模型是我们综合生物学策略的一个关键方面，因此我们利用基因敲除（例如 p53 和诱导型一氧化氮合酶）来研究炎症相关癌症的机制。 NO∙ 的适度增加会导致生长停滞和细胞凋亡，从而延缓肿瘤形成，而较高的 NO∙ 量则与炎症和肿瘤形成增加有关。我们还将探讨肥胖增加的癌症风险与促炎症状态有关的假设。