title: Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis.
abstract: Nrf2 (Nfe2l2) governs cellular defenses against oxidative and electrophilic stresses and protects against chemical carcinogenesis. However, many cancers have been found to accumulate NRF2 protein, raising questions of precisely how Nrf2 contributes to carcinogenesis. In this report, we explored such questions in an established urethane-induced multistep model of lung carcinogenesis. Consistent with earlier observations, Nrf2-deficient (Nrf2(-/-)) mice exhibited a relative increase in tumor foci by 8 weeks after urethane administration. However, after 16 weeks, we observed a relative reduction in the number of tumors with more malignant characteristics in Nrf2(-/-) mice. Furthermore, all Nrf2(+/+) tumors harbored activated mutations in Kras, whereas Nrf2(-/-) tumors were rarely associated with similar Kras mutations. Overall, our results established that Nrf2 has two roles during carcinogenesis, one of which is preventive during tumor initiation and the second that promotes malignant progression. These findings establish Nrf2 inhibitors as rational tools to prevent malignant progression in lung cancer, whereas Nrf2 activators are more suited for lung cancer prevention.
authors.affiliation: Department of Medical Biochemistry and Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Satoh
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.forename: Jun
authors.initials: J
authors.lastname: Takai
authors.forename: Masahito
authors.initials: M
authors.lastname: Ebina
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008819:Mice, Nude; D009154:Mutation; D022423:Myeloid Cells / Q000276:immunology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D059467:Transcriptome; D047368:Tumor Burden; D019139:Tumor Escape; D014520:Urethane
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D014520:Urethane; D019392:Cytochrome P-450 CYP2E1; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)