Inflammation and Cancer

自由基在我们的身体中普遍存在，由正常的生理过程产生，包括有氧代谢和炎症反应，以消除入侵的病原微生物。慢性炎症会增加患癌症的风险。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过程中的一个重要途径。我们已经证明，P53肿瘤抑制网络是慢性炎症应激的微环境成分的关键反应者，包括一氧化氮、羟基离子、低氧以及由于内源性自由基对DNA的破坏而导致的DNA复制受阻。慢性炎症激活P53肿瘤抑制网络，并通过P53突变使其失活。此外，慢性炎症通过Rb蛋白的过度磷酸化使Rb肿瘤抑制网络失效，从而允许E2F1转录因子的释放。我们还比较了炎症在溃疡性结肠炎和克罗恩病结肠癌发生中的作用。动物模型是我们综合生物学战略的关键方面，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以延缓肿瘤的形成，而较高的NO含量与炎症和肿瘤形成的增加有关。我们还将探索这样的假设，即肥胖导致的癌症风险增加与促炎状态有关。

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 the p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress including nitric oxide, hydroxyl ions, hypoxia, and DNA replication arrest due to DNA damage by endogenous free radicals. Chronic inflammation activates the p53 tumor suppressor network and inactivates it by mutation of p53. In addition, chronic inflammation disables the RB tumor suppressor network by hyperphosphorylation of the RB protein, allowing the release of the E2F1 transcription factor. We are also 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.