title: NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates Malignant Cell Growth.
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.
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan. Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Satoh
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan. masiyamamoto@med.tohoku.ac.jp moriguch@med.tohoku.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank, Tohoku University, Aoba-ku, Sendai, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saigusa
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Liam
authors.initials: L
authors.lastname: Baird
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Rokutan
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Department of Respiratory Medicine, Pulmonary Center, Tohoku Pharmaceutical University Hospital, Miyagino-ku, Sendai, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Ebina
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan. masiyamamoto@med.tohoku.ac.jp moriguch@med.tohoku.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D014520:Urethane / Q000633:toxicity
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D014520:Urethane