Nrf2 knockout enhances intestinal tumorigenesis in Apc^min/+ mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation

Mutations in adenomatous polyposis coli (APC) gene are found in more than 80% of colorectal cancer (CRC) patients. The nuclear transcription factor Nrf2 plays a central role in the regulation of oxidative stress and inflammation. Previously, we have shown that chronic inflammation in Nrf2^-/- (Nrf2 knockout; KO) mice resulted in higher expression of inflammatory markers and cytokines, coupled with higher inflammatory damage to the colonic crypt cells, as compared to the Nrf2^+/+ (wild type; WT) mice. Induction of mutation in the colon by administration of carcinogen, AOM prior to DSS-induced inflammation resulted in higher tumor incidence and numbers in Nrf2KO mice. These results indicate that Nrf2-dependent inhibition of inflammation appears to be critical in inhibiting mutation-initiated colorectal carcinogenesis. In this study, we aim to investigate if loss of Nrf2 would dose-dependently promote intestinal tumorigenesis in Apc^min/+ mice. To demonstrate the in vivo mechanisms, we constructed both Apc mutated and Nrf2 deficient strain Apc^min/+ mice with C57BL/6 Nrf2KO mice to obtain F1, Apc^min/+;Nrf2^+/- and F2, Apc^min/+;Nrf2^-/-mice. Nrf2KO decreased the protein expression of antioxidant enzyme NQO1 in Apc^min/+. In contrast, Nrf2KO enhanced the expression of inflammatory markers such as COX-2, cPLA, LTB₄ in Apc^min/+. Finally, Nrf2KO resulted in higher level of PCNA and c-Myc expression in intestinal tissue, indicating the deficiency of Nrf2 promotes proliferation of intestinal crypt cells in Apc^min/+. Taken together, our results suggest that Nrf2KO attenuates anti-oxidative stress pathway, induces inflammation, and increases proliferative potential in the intestinal crypts leading to enhanced intestinal carcinogenesis and adenomas in Apc^min/+.