Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer.
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.
Khor
Tin Oo
TO
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.
Huang
Mou-Tuan
MT
Prawan
Auemduan
A
Liu
Yue
Y
Hao
Xingpei
X
Yu
Siwang
S
Cheung
William Ka Lung
WK
Chan
Jefferson Y
JY
Reddy
Bandaru S
BS
Yang
Chung S
CS
Kong
Ah-Ng
AN
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*
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016264:Dextran Sulfate; D051546:Cyclooxygenase 2; D001397:Azoxymethane