Nrf2 Knockout Enhances Intestinal Tumorigenesis in Apcmin Mice Due to Attenuation of Anti-Oxidative Stress Pathway While Potentiates Inflammation

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

来源：Molecular Carcinogenesis, 2014, 53(1): 77-84.

DOI：10.1002/mc.21950

• Nrf2
• Apc(min)
• colon carcinogenesis
• oxidative stress
• 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/+).

• 出版日期2014-1