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.

Requirement and Epigenetics Reprogramming of Nrf2 in Suppression of Tumor Promoter TPA-Induced Mouse Skin Cell Transformation by Sulforaphane

“…By binding to an antioxidant response element (ARE) in the promoter region of a target gene, nuclear Nrf2 induces the expression of antioxidative stress/detoxifying enzymes, such as heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase-1 (NQO-1), UDP-glucuronosyltransferase (UGT), and glutathione-S-transferase (GST; 6, 7). It has been reported that the susceptibility to tumorigenesis induced by a carcinogen is higher in Nrf2-deficient mice (8,9), and cancer chemoprevention is partially correlated with the induction of phase II enzymes (10,11). Our recent study demonstrated that the expression of Nrf2 can be regulated by epigenetic alterations in both the prostate tissue of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model and tumorigenic TRAMP C1 cells (12).…”

Nrf2 target genes are induced under marginal selenium-deficiency

“…The activation of the Nrf2 pathway in marginal selenium-deficiency is relevant in terms of colorectal cancer development. In a model of inflammation-triggered colorectal carcinogenesis, Nrf2 -/-mice showed an increased incidence, multiplicity and tumor size compared to wild type mice [25]. On the one hand, phase II enzymes like the GST, SULT and UGT family are involved in the conjugation and excretion of xenobiotic substances.…”

Luteolin, a Bioflavonoid Inhibits Colorectal Cancer through Modulation of Multiple Signaling Pathways: A Review

“…It is difficult to discuss the cancer chemoprevention without mentioning Nrf2 transcription factor, since the discovery of Nrf2 is attributed greatly to studies with anti-carcinogenic compounds (Zhang, 2006).There are many reports stating that Nrf2-deficient mice are more susceptible to toxicity, DNA adduct formation and cancer development in several models of chemical-induced carcinogenesis (Xu et al, 2006;Khor et al, 2008). Nrf2-null mice have decreased basal and inducible expression of antioxidant genes, increased oxidative stress, and decreased reducing activity and antioxidant capacity (Chan et al, 2000;Hirayama et al, 2003), suggesting that the Nrf2/ARE pathway is crucial in the regulation of intracellular redox status.…”