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. 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.
| Stauffer, Jimmy K; Scarzello, Anthony J; Jiang, Qun et al. (2012) Chronic inflammation, immune escape, and oncogenesis in the liver: a unique neighborhood for novel intersections. Hepatology 56:1567-74 |
| Simone, Nicole L; Soule, Benjamin P; Ly, David et al. (2009) Ionizing radiation-induced oxidative stress alters miRNA expression. PLoS One 4:e6377 |
| Hussain, S Perwez; He, Peijun; Subleski, Jeffery et al. (2008) Nitric oxide is a key component in inflammation-accelerated tumorigenesis. Cancer Res 68:7130-6 |
| Thomas, Douglas D; Ridnour, Lisa A; Isenberg, Jeffrey S et al. (2008) The chemical biology of nitric oxide: implications in cellular signaling. Free Radic Biol Med 45:18-31 |
| Wink, David A; Ridnour, Lisa A; Hussain, S Perwez et al. (2008) The reemergence of nitric oxide and cancer. Nitric Oxide 19:65-7 |
| Thomas, Douglas D; Ridnour, Lisa A; Espey, Michael Graham et al. (2006) Superoxide fluxes limit nitric oxide-induced signaling. J Biol Chem 281:25984-93 |
| Goodman, Julie E; Mechanic, Leah E; Luke, Brian T et al. (2006) Exploring SNP-SNP interactions and colon cancer risk using polymorphism interaction analysis. Int J Cancer 118:1790-7 |
| Ying, Lei; Marino, Jillian; Hussain, S Perwez et al. (2005) Chronic inflammation promotes retinoblastoma protein hyperphosphorylation and E2F1 activation. Cancer Res 65:9132-6 |
| Hofseth, Lorne J; Robles, Ana I; Espey, Michael G et al. (2005) Nitric oxide is a signaling molecule that regulates gene expression. Methods Enzymol 396:326-40 |
| Hussain, S Perwez; Trivers, Glennwood E; Hofseth, Lorne J et al. (2004) Nitric oxide, a mediator of inflammation, suppresses tumorigenesis. Cancer Res 64:6849-53 |
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