The long-term goal of this project is to provide a mechanistic basis for the prevention of Ulcerative colitis (UC)-associated carcinogenesis (UC-Ca). Our unique UC-Ca mouse model will be used to test the hypothesis that leukocyte-NADPH oxidase and endothelial nitric oxide synthase (eNOS) play central roles in UC-Ca by driving nitro-oxidative stress-caused genetic damage and angiogenesis, and by causing cell hyperproliferation via the overproduction of prostaglandin E2 (PGE2) and Leukotriene B4 (LTB4), with the following specific aims: 1. To study the role of leukocyte-generated oxidative stress and associated DNA damage in UC-Ca by using gp91phox (leukocyte NADPH oxidase) and Ogg1 (8-hydroxydeoxyguanine DNA glycosylase) deficient mice. We will test the hypothesis that gp91phox is vital for causing oxidative DNA damage and UC-Ca, and that Ogg1 protects from UC-Ca, using gene knockout mice in the UC-Ca model. 2. To test the hypothesis that eNOS plays a key role in UC-Ca by driving nitro-oxidative stress-caused DNA damage and by promoting angiogenesis, iNOS deficient mice exhibited no difference in susceptibility to UC-Ca or nitrotyrosine formation in our model, but eNOS was expressed in active inflammatory cells. The roles of eNOS or both eNOS/iNOS in UC-Ca will be studied using an eNOS (-/-)mice and the non-selective NOS inhibitor aminoguanidine. 3. To test the hypothesis that inflammation-induced LTB4 and PGE2 overproduction contributes to UCCa by studying the effect of the combination of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5- LOX) inhibitors. COX-2 inhibition exacerbates UC, possibly via the shunting of arachidonic acid substrate to the LTB4 pathway and increasing inflammatory injury. The combination of 5-LOX- and COX-2-specific inhibitors may overcome this problem in the treatment of UC patients. This concept will be tested in our UC-Ca model. 4. To determine the effectiveness of water-soluble and lipid-soluble antioxidants and their combination as a chemopreventive approach against UC-Ca in wild type and Ogg1(-/-) mice. The combination of vitamin E and N-acetylcysteine (NAC) may exert synergistic or additive effects against nitro-oxidative stress, inflammation, and UC-Ca. This concept will be investigated using our UC-Ca model as well as using Ogg1 knockout mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA104741-03
Application #
7106997
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2005-08-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$238,690
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Zhang, Wanying; Liao, Jie; Li, Haonan et al. (2013) Reduction of inflammatory bowel disease-induced tumor development in IL-10 knockout mice with soluble epoxide hydrolase gene deficiency. Mol Carcinog 52:726-38
Chung, Yeon Tae; Matkowskyj, Kristina A; Li, Haonan et al. (2012) Overexpression and oncogenic function of aldo-keto reductase family 1B10 (AKR1B10) in pancreatic carcinoma. Mod Pathol 25:758-66
Yang, Guang-Yu; Taboada, Sofia; Liao, Jie (2009) Induced nitric oxide synthase as a major player in the oncogenic transformation of inflamed tissue. Methods Mol Biol 512:119-56
Yang, Guang-Yu; Taboada, Sofia; Liao, Jie (2009) Inflammatory bowel disease: a model of chronic inflammation-induced cancer. Methods Mol Biol 511:193-233
Liao, Jie; Seril, Darren N; Lu, Gary G et al. (2008) Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice. Mol Carcinog 47:638-46
Seril, Darren N; Liao, Jie; Yang, Guang-Yu (2007) Colorectal carcinoma development in inducible nitric oxide synthase-deficient mice with dextran sulfate sodium-induced ulcerative colitis. Mol Carcinog 46:341-53
Liao, Jie; Seril, Darren N; Yang, Allison L et al. (2007) Inhibition of chronic ulcerative colitis associated adenocarcinoma development in mice by inositol compounds. Carcinogenesis 28:446-54
Seril, Darren N; Liao, Jie; West, Alexander Brian et al. (2006) High-iron diet: foe or feat in ulcerative colitis and ulcerative colitis-associated carcinogenesis. J Clin Gastroenterol 40:391-7
Seril, Darren N; Liao, Jie; Yang, Chung S et al. (2005) Systemic iron supplementation replenishes iron stores without enhancing colon carcinogenesis in murine models of ulcerative colitis: comparison with iron-enriched diet. Dig Dis Sci 50:696-707