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/+) .
Graduate Program in Pharmaceutical Science, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Center for Cancer Prevention Research, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
Ka Lung
KL
Cheung
Jong Hun
JH
Lee
Tin Oo
TO
Khor
Tien-Yuan
TY
Wu
Guang Xun
GX
Li
Jefferson
J
Chan
Chung S
CS
Yang
Ah-Ng Tony
AN
Kong
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007417:Intestinal Polyps / Q000235:genetics / Q000473:pathology; D007422:Intestines / Q000473:pathology; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D015398:Signal Transduction
D025601:Adenomatous Polyposis Coli Protein; D051267:NF-E2-Related Factor 2; D007975:Leukotriene B4; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human