Effects of Nrf2 silencing on oxidative stress-associated intestinal carcinogenesis in mice

Abstract

To assess the risk of colorectal cancer in humans with inactivation of NRF2, Nrf2-proficient (Nrf2^+/+) and -deficient (Nrf2^−/−) mice were exposed to potassium bromate (KBrO₃) at concentrations of 750 or 1500 ppm for 52 weeks. Neoplastic proliferative lesions were observed in the small intestine and exhibited accumulations of β-catenin and cyclin D1. The lesions had characteristics similar to those in experimental models of human hereditary colorectal cancer. An additional 13-week study was performed to examine the role of Nrf2 in the effects of oxidative stress. Significant increase in combined incidences of preneoplastic and neoplastic lesions in Nrf2^−/− mice administered high-dose KBrO₃. In the short-term study, although 8-hydroxydeoxyguanosine (8-OHdG) levels in the epithelial DNA of Nrf2^−/− mice at the high dose were significantly lower than those of the corresponding Nrf2^+/+ mice, the difference was very small. mRNA levels of Nrf2-regulated genes were increased in Nrf2^+/+ mice. Overexpression of cyclooxygenase 2 (COX2) and increased numbers of proliferating cell nuclear antigen (PCNA)-positive cells in the jejunal crypts were observed in Nrf2^−/− mice administered high-dose KBrO₃. Overall, these data suggested that individuals having single-nucleotide polymorphisms in NRF2 may have a risk of colorectal cancer to some extent.

Nrf2 deficiency increased susceptibility to oxidative stress-induced small intestinal carcinogenesis in mice, in which COX2 overexpression followed by cell-cycle progression was involved. Individuals having single-nucleotide polymorphisms in NRF2 may have a risk of colorectal cancer to some extent.

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