title: Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer.
abstract: The nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a critical role in protecting various tissues against inflammation, which is a potential risk factor for colorectal and other cancers. Our previously published mouse model work showed that Nrf2 helps protect against dextran sulfate sodium (DSS)-induced colitis/inflammation, and others have shown that Nrf2 helps protect against inflammation-associated colorectal carcinogenesis (aberrant crypt foci). The present study extended these important earlier findings by exploring the role of Nrf2 in colitis-associated colorectal cancer in a mouse model involving azoxymethane/DSS-induced colorectal carcinogenesis in Nrf2 knockout mice. Azoxymethane/DSS-treated Nrf2 knockout mice had increased incidence, multiplicity, and size of all colorectal tumors, including adenomas, versus treated wild-type (WT) mice, and the proportion of tumors that were adenocarcinoma was much higher in knockout (80%) versus WT (29%) mice. Compared with WT mice, knockout mice also had increased markers of inflammation in tumor tissue (cyclooxygenase-2 and 5-lipoxygenase expressions and prostaglandin E(2) and leukotriene B(4) levels) and in inflamed colonic mucosa (nitrotyrosine expression), supporting the association of knockout mouse tumor formation with inflammation. The phase II detoxifying/antioxidant enzymes NAD(P)H-quinone reductase 1 and UDP-glucurosyltransferase 1A1 were elevated in the normal mucosa of WT, but not Nrf 2 knockout, mice treated with azoxymethane/DSS. Our findings show that Nrf2 plays a critical role in protecting against inflammation-associated colorectal cancer.
authors.affiliation: Center for Cancer Prevention Research and Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
authors.forename: Tin Oo
authors.initials: TO
authors.lastname: Khor
authors.forename: Mou-Tuan
authors.initials: MT
authors.lastname: Huang
authors.forename: Auemduan
authors.initials: A
authors.lastname: Prawan
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.forename: Xingpei
authors.initials: X
authors.lastname: Hao
authors.forename: Siwang
authors.initials: S
authors.lastname: Yu
authors.forename: William Ka Lung
authors.initials: WK
authors.lastname: Cheung
authors.forename: Jefferson Y
authors.initials: JY
authors.lastname: Chan
authors.forename: Bandaru S
authors.initials: BS
authors.lastname: Reddy
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.forename: Ah-Ng
authors.initials: AN
authors.lastname: Kong
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D000236:Adenoma / Q000139:chemically induced / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D000818:Animals; D001397:Azoxymethane; D003092:Colitis / Q000150:complications / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000235:genetics; D019610:Cytoprotection / Q000235:genetics; D016264:Dextran Sulfate; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016264:Dextran Sulfate; D051546:Cyclooxygenase 2; D001397:Azoxymethane