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Updated: Mar 23, 2026
Protein Transfection of Mouse Lung
Published on: May 15, 2013
NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates
Hironori Satoh1, Takashi Moriguchi2, Daisuke Saigusa3
1Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan. Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Abstract:
Nrf2 activation promotes resistance to chemical carcinogenesis in animal models, but activating mutations in Nrf2 also confer malignant characters to human cells by activating antioxidative/detoxifying enzymes and metabolic reprogramming. In this study, we examined how these contradictory activities of Nrf2, cancer chemoprevention and cancer cell growth enhancement, can be reconciled in an established mouse model of urethane-induced lung carcinogenesis. Using Keap1-knockdown (kd) mice, which express high levels of Nrf2, we found that urethane was rapidly excreted into the urine, consistent with an upregulation in the expression of urethane detoxification genes. Consequently, urethane-induced tumors were significantly smaller and less frequent in Keap1-kd mice than in wild-type mice. In contrast, tumor cells derived from Keap1-kd mice and transplanted into nude mice exhibited higher tumorigenicity compared with cells derived from wild-type mice. To identify the factors contributing to the tumor growth phenotype in the transplantation model, we performed a microarray analysis and found that many antioxidative stress genes were upregulated in the Keap1-kd-derived tumors. Therefore, we suggest that Nrf2 activation in cancer cells enhances their tumorigenicity, but global Nrf2 activation, as in Keap1-kd mice, simultaneously enhances anticancer immunity, thereby suppressing the growth potential of Keap1-kd tumors. Our findings provide relevant insight into the dual role of Nrf2 in cancer and warrant further studies of Nrf2 function during different stages of carcinogenesis. Cancer Res; 76(10); 3088-96. ©2016 AACR.
Insights
High Nrf2 levels protect against lung cancer by enhancing detoxification. However, Nrf2 also promotes tumor growth, suggesting a complex role in cancer development and immunity.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) activation has dual roles in cancer: chemoprevention and promoting malignant characteristics.
- Understanding Nrf2's contradictory functions is crucial for cancer therapy development.
- This study investigates Nrf2's role in urethane-induced lung carcinogenesis in mice.
Purpose of the Study:
- To reconcile the opposing roles of Nrf2 in cancer chemoprevention and cancer cell growth.
- To examine the impact of global Nrf2 activation on lung tumor development and progression.
- To elucidate the mechanisms underlying Nrf2's dual effects in a carcinogenesis model.
Main Methods:
- Utilized Keap1-knockdown (kd) mice with high Nrf2 expression.
- Administered urethane to induce lung carcinogenesis.
- Assessed tumor incidence and size in Keap1-kd and wild-type mice.
- Performed tumor cell transplantation into nude mice to evaluate tumorigenicity.
- Conducted microarray analysis to identify differentially expressed genes in tumors.
Main Results:
- Keap1-kd mice showed rapid urethane excretion and reduced tumor frequency/size due to enhanced detoxification.
- Tumor cells derived from Keap1-kd mice exhibited increased tumorigenicity in transplantation models.
- Microarray analysis revealed upregulation of antioxidative stress genes in Keap1-kd-derived tumors.
Conclusions:
- Nrf2 activation enhances cancer cell tumorigenicity but also boosts anticancer immunity when globally activated.
- Global Nrf2 activation suppresses tumor growth potential by enhancing anticancer immunity.
- Nrf2 plays a complex, stage-dependent role in carcinogenesis, requiring further investigation.
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