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Increased Susceptibility of Nrf2 Knockout Mice to Colitis-Associated Colorectal Cancer
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Abstract
The nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a critical role in protecting various tissues against inflammation, which is a potential risk factor for colorectal and other cancers. Our previously published mouse model work showed that Nrf2 helps protect against dextran sulfate sodium (DSS)-induced colitis/inflammation, and others have shown that Nrf2 helps protect against inflammation-associated colorectal carcinogenesis (aberrant crypt foci). The present study extended these important earlier findings by exploring the role of Nrf2 in colitis-associated colorectal cancer in a mouse model involving azoxymethane/DSS-induced colorectal carcinogenesis in Nrf2 knockout mice. Azoxymethane/DSS-treated Nrf2 knockout mice had increased incidence, multiplicity, and size of all colorectal tumors, including adenomas, versus treated wild-type (WT) mice, and the proportion of tumors that were adenocarcinoma was much higher in knockout (80%) versus WT (29%) mice. Compared with WT mice, knockout mice also had increased markers of inflammation in tumor tissue (cyclooxygenase-2 and 5-lipoxygenase expressions and prostaglandin E(2) and leukotriene B(4) levels) and in inflamed colonic mucosa (nitrotyrosine expression), supporting the association of knockout mouse tumor formation with inflammation. The phase II detoxifying/antioxidant enzymes NAD(P)H-quinone reductase 1 and UDP-glucurosyltransferase 1A1 were elevated in the normal mucosa of WT, but not Nrf 2 knockout, mice treated with azoxymethane/DSS. Our findings show that Nrf2 plays a critical role in protecting against inflammation-associated colorectal cancer.
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“Our data show that tissue and plasma from Nrf2KO mice present higher levels of inflammation at 4 month of age (measured by the cytokine levels), corroborating previous reports (Ishii et al., 2005; Khor et al., 2008).”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Khor et al., 2008
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Metadata
- Authors
- Khor, T. O., Huang, M.-T., Prawan, A., Liu, Y., Hao, X., Yu, S., Cheung, W. K. L., Chan, J. Y., Reddy, B. S., Yang, C. S., & Kong, A.-N.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Kong, Ah-Ng
- Venue
- Cancer Prevention Research
- Published
- 2008-07-25
- Volume
- 1
- Issue
- 3
- Pages
- 187-191
- ISSN
- 1940-6207 (ISSN-L)
- 1940-6215
- PMC
- PMC3580177
- OpenAlex
- W2141004419
- Cited by
- 306
- References
- 22
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 9 · 2023: 17 · 2022: 18 · 2021: 10 · 2020: 23 · 2019: 28 · 2018: 21 · 2017: 34 · 2016: 22 · 2015: 22 · 2014: 18 · 2013: 16 · 2012: 16
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Prevention Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA073674)
- National Institute of Environmental Health Sciences (P30ES005022)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- Nrf2, colitis-associated colorectal cancer, Nrf2 knockout mice, inflammation-associated carcinogenesis, colorectal adenoma, cyclooxygenase-2, 5-lipoxygenase, prostaglandin E2, leukotriene B4, nitrotyrosine, UDP-glucuronosyltransferase 1A1, phase II enzymes, antioxidant defense
- MeSH terms
- Adenocarcinoma, Adenoma, Animals, Azoxymethane, Colitis, Male, Mice, Inbred C57BL, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Dextran Sulfate, Mice, Knockout, Cytoprotection, Genetic Predisposition to Disease, NF-E2-Related Factor 2, Mice, Cyclooxygenase 2
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