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Title: Nrf2 knockout enhances intestinal tumorigenesis in Apc(min/+) mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation.

Authors: Cheung, Ka Lung; Lee, Jong Hun; Khor, Tin Oo; Wu, Tien-Yuan; Li, Guang Xun; Chan, Jefferson; Yang, Chung S; Kong, Ah-Ng Tony

Published In Mol Carcinog, (2014 Jan)

Abstract: 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/+) .

PubMed ID: 22911891 Exiting the NIEHS site

MeSH Terms: Adenomatous Polyposis Coli Protein/genetics*; Animals; Cell Proliferation; Cell Transformation, Neoplastic/genetics*; Cell Transformation, Neoplastic/metabolism*; Colorectal Neoplasms/genetics; Colorectal Neoplasms/metabolism; Gene Knockout Techniques; Inflammation/genetics; Inflammation/metabolism; Inflammation/pathology; Intestinal Polyps/genetics; Intestinal Polyps/pathology; Intestines/metabolism*; Intestines/pathology; Leukotriene B4/metabolism; Male; Mice; Mice, Knockout; NAD(P)H Dehydrogenase (Quinone)/genetics; NAD(P)H Dehydrogenase (Quinone)/metabolism; NF-E2-Related Factor 2/genetics*; Oxidative Stress/genetics*; Signal Transduction*

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