title: Roles of Keap1-Nrf2 system in upper aerodigestive tract carcinogenesis.
abstract: Cancers in the upper aerodigestive tract, including cancers of the tongue and the esophagus, are the third leading cause of cancer-related deaths in the world, and oxidative stress is well recognized as one of the major risk factors for carcinogenesis. The Keap1-Nrf2 system plays a critical role in cellular defense against oxidative stress, but little is known about its association with upper aerodigestive tract carcinogenesis. In this study, we examined whether loss of Nrf2-function exacerbates carcinogenesis by using an experimental carcinogenesis model that is induced by 4-nitroquinoline-1-oxide (4NQO). We found that Nrf2-knockout (Nrf2-KO) mice were more susceptible to 4NQO-induced tongue and esophageal carcinogenesis than wild-type mice, which suggests that Nrf2 is important for cancer prevention. We also examined how the suppression of Keap1 function or the induction of Nrf2 activity affected 4NQO carcinogenesis. Keap1-knockdown (Keap1-KD) mice were resistant to 4NQO-induced tongue and esophageal carcinogenesis. Importantly, no growth advantage was observed in tongue tumors in the Keap1-KD mice. These results show that the Keap1-Nrf2 system regulates an important defense mechanism against upper aerodigestive tract carcinogenesis. In addition to several important functions of Nrf2 that lead to cancer chemoprevention, we hypothesize that a mechanical defense of thickened keratin layers may also be a chemopreventive factor because thickened, stratified, squamous epithelium was found on the tongue of Keap1-KD mice.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohkoshi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masao
authors.initials: M
authors.lastname: Ono
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015112:4-Nitroquinoline-1-oxide