Abstract 5702: Soluble epoxide hydrolase: unique biomarker and chemopreventive target of chronic colitis-induced carcinogenesis

Abstract

Abstract Chronic ulcerative colitis (UC) is a well-recognized risk factor of colon cancer; aberrant arachidonic acid (AA) metabolism in UC is a key event leading to cancer development. Epoxyeicosatrienoic acids (EETs) are AA metabolites with anti-inflammatory activity; under physiological conditions, EETs are quickly inactivated as they are converted to their corresponding dihydroxyeicosatrienoic acids (DHETs) by the enzyme soluble epoxide hydrolase (sEH). The inhibition of sEH retards hydrolysis of the epoxide, reducing the conversion of EETs to DHETs. Thus, sEH would be a unique target for colitis. However, the role of sEH in chronic colitis and its associated carcinogenesis is not known. In the present study, we have determined if the sEH over-expresses in human ulcerative colitis and its associated dysplasia and carcinoma. Tissue microarrays contained 180 patients (4 tissue samples/patient) with UC (72 patients), UC-dysplasia (54 patients), and UC-carcinoma (54 patients) were established. Using specific anti-sEH antibody and immunohistochemistry approach, distinct expression of sEH was found in the microarray samples. Normal colon displayed weak positivity in 39.1% (n=79), mainly in the focally reactive epithelia. In UC, 74.6% (n=72) displayed positivity, extensively expressed in the hyperplastic epithelia. 88.2% (n=54) of colitis-induced dysplasia and 93.9% (n=54) of colitis-induced carcinoma displayed positivity. Markedly increased sEH staining intensity was observed in UC-induced dysplasia and carcinoma. Secondly, the effect of highly selective and potent sEH inhibitor, trans/−4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), on chronic colitis-induced carcinoma development was determined in IL-10 knockout mice. t-AUCB was administered to IL-10 KO mice in the drinking fluid for three months with the doses of 1.25mg/kg and 2.5 mg/kg body weight (n=10 mice per group). Both low and high doses of t-AUCB significantly suppressed body weight reduction caused by colitis. Histopathologic analysis revealed that there were 80% tumor incidence (8/10 mice) in IL-10 colitis control mice; low and high doses of t-AUCB significantly inhibited the colitis-induced carcinoma development with tumor incidence 10% (1/10 mice) and 40% (4/10 mice), respectively. The tumor volume was markedly reduced (0.062 ± 0.019 cm3 in IL-10 KO colitis mice versus 0.026 ± 0.008 and 0.014 ± 0.012 cm3 in IL-10 KO colitis mice treated with low and high doses of t-AUCB, respectively). The results indicate that sEH is a crucial enzyme over-expressed in human colitis-induced carcinogenesis, and sEH inhibitor is an efficient approach for chemoprevention. (Supported by NIH CA137467 grant). Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5702.