論文

国際誌
2022年9月15日

Selective Elimination of NRF2-Activated Cells by Competition With Neighboring Cells in the Esophageal Epithelium

Cellular and Molecular Gastroenterology and Hepatology
  • Wataru Hirose
  • ,
  • Makoto Horiuchi
  • ,
  • Donghan Li
  • ,
  • Ikuko N. Motoike
  • ,
  • Lin Zhang
  • ,
  • Hafumi Nishi
  • ,
  • Yusuke Taniyama
  • ,
  • Takashi Kamei
  • ,
  • Mikiko Suzuki
  • ,
  • Kengo Kinoshita
  • ,
  • Fumiki Katsuoka
  • ,
  • Keiko Taguchi
  • ,
  • Masayuki Yamamoto

15
1
開始ページ
153
終了ページ
178
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.jcmgh.2022.09.004
出版者・発行元
Elsevier BV

BACKGROUND & AIMS: NF-E2-related factor 2 (NRF2) is a transcription factor that regulates cytoprotective gene expression in response to oxidative and electrophilic stresses. NRF2 activity is mainly controlled by Kelch-like ECH-associated protein 1 (KEAP1). Constitutive NRF2 activation by NRF2 mutations or KEAP1 dysfunction results in a poor prognosis for esophageal squamous cell carcinoma (ESCC) through the activation of cytoprotective functions. However, the detailed contributions of NRF2 to ESCC initiation or promotion have not been clarified. Here, we investigated the fate of NRF2-activated cells in the esophageal epithelium. METHODS: We generated tamoxifen-inducible, squamous epithelium-specific Keap1 conditional knockout (Keap1-cKO) mice in which NRF2 was inducibly activated in a subset of cells at the adult stage. Histologic, quantitative reverse-transcription polymerase chain reaction, single-cell RNA-sequencing, and carcinogen experiments were conducted to analyze the Keap1-cKO esophagus. RESULTS: KEAP1-deleted/NRF2-activated cells and cells with normal NRF2 expression (KEAP1-normal cells) coexisted in the Keap1-cKO esophageal epithelium in approximately equal numbers, and NRF2-activated cells formed dysplastic lesions. NRF2-activated cells exhibited weaker attachment to the basement membrane and gradually disappeared from the epithelium. In contrast, neighboring KEAP1-normal cells exhibited accelerated proliferation and started dominating the epithelium but accumulated DNA damage that triggered carcinogenesis upon carcinogen exposure. CONCLUSIONS: Constitutive NRF2 activation promotes the selective elimination of epithelial cells via cell competition, but this competition induces DNA damage in neighboring KEAP1-normal cells, which predisposes them to chemical-induced ESCC.

リンク情報
DOI
https://doi.org/10.1016/j.jcmgh.2022.09.004
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/36115578
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9672893
ID情報
  • DOI : 10.1016/j.jcmgh.2022.09.004
  • ISSN : 2352-345X
  • PubMed ID : 36115578
  • PubMed Central 記事ID : PMC9672893

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