Related Experiment Video
Updated: Mar 25, 2026
Analyzing Oxidative Stress in Murine Intestinal Organoids using Reactive Oxygen Species-Sensitive Fluorogenic Probe
Published on: September 17, 2021
Effects of Nrf2 silencing on oxidative stress-associated intestinal carcinogenesis in mice
Yuh Yokoo1, Aki Kijima1, Yuji Ishii1
1Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
Abstract:
To assess the risk of colorectal cancer in humans with inactivation of NRF2, Nrf2-proficient (Nrf2(+/+) ) and -deficient (Nrf2(-/-) ) mice were exposed to potassium bromate (KBrO3 ) at concentrations of 750 or 1500 ppm for 52 weeks. Neoplastic proliferative lesions were observed in the small intestine and exhibited accumulations of β-catenin and cyclin D1. The lesions had characteristics similar to those in experimental models of human hereditary colorectal cancer. An additional 13-week study was performed to examine the role of Nrf2 in the effects of oxidative stress. Significant increase in combined incidences of preneoplastic and neoplastic lesions in Nrf2(-/-) mice administered high-dose KBrO3 . In the short-term study, although 8-hydroxydeoxyguanosine (8-OHdG) levels in the epithelial DNA of Nrf2(-/-) mice at the high dose were significantly lower than those of the corresponding Nrf2(+/+) mice, the difference was very small. mRNA levels of Nrf2-regulated genes were increased in Nrf2(+/+) mice. Overexpression of cyclooxygenase 2 (COX2) and increased numbers of proliferating cell nuclear antigen (PCNA)-positive cells in the jejunal crypts were observed in Nrf2(-/-) mice administered high-dose KBrO3 . Overall, these data suggested that individuals having single-nucleotide polymorphisms in NRF2 may have a risk of colorectal cancer to some extent.
Insights
Mice lacking NRF2 (nuclear factor erythroid 2-related factor 2) showed increased risk of colorectal cancer when exposed to potassium bromate. This suggests NRF2 genetic variations may influence human colorectal cancer susceptibility.
Area of Science:
- Oncology
- Molecular Biology
- Toxicology
Background:
- The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is crucial for cellular defense against oxidative stress.
- Dysregulation of NRF2 has been implicated in various cancers, including colorectal cancer (CRC).
Purpose of the Study:
- To investigate the role of NRF2 in the development of colorectal cancer using a mouse model.
- To assess the carcinogenic potential of potassium bromate (KBrO3) and its interaction with NRF2 status.
Main Methods:
- Nrf2-proficient (Nrf2(+/+)) and Nrf2-deficient (Nrf2(-/-)) mice were chronically exposed to potassium bromate (KBrO3) for 52 weeks.
- A 13-week study examined oxidative stress markers and gene expression in response to KBrO3.
- Histopathological analysis identified neoplastic lesions and assessed markers like beta-catenin, cyclin D1, 8-hydroxydeoxyguanosine (8-OHdG), cyclooxygenase 2 (COX2), and proliferating cell nuclear antigen (PCNA).
Main Results:
- Nrf2(-/-) mice exhibited a significant increase in preneoplastic and neoplastic lesions in the small intestine after KBrO3 exposure.
- Lesions showed accumulations of beta-catenin and cyclin D1, resembling human hereditary colorectal cancer.
- Overexpression of COX2 and increased PCNA-positive cells were observed in Nrf2(-/-) mice, indicating heightened proliferation and inflammation.
Conclusions:
- NRF2 deficiency exacerbates KBrO3-induced intestinal tumorigenesis, suggesting a protective role for NRF2 in colorectal cancer prevention.
- These findings indicate that genetic variations in NRF2 may contribute to an individual's susceptibility to colorectal cancer.
