ArticleCellular and molecular gastroenterology and hepatology2023
Selective Elimination of NRF2-Activated Cells by Competition With Neighboring Cells in the Esophageal Epithelium.
Article in Cellular and molecular gastroenterology and hepatology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 12 citations in OpenAlex.
- GSTT2 Switches from a Homeostatic Antioxidant to a Cell-Cycle-Coupled Factor in Therapy-Resistant Esophageal Adenocarcinoma.Cancers · 2026Article
- Esophageal cancer: from pathogenesis to precision therapies.Signal transduction and targeted therapy · 2026Review
- Oxygen needs sulfur, sulfur needs oxygen: a relationship of interdependence.The EMBO journal · 2025Review
- Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases.Redox biology · 2025Review
- Human-Specific Organization of Proliferation and Stemness in Squamous Epithelia: A Comparative Study to Elucidate Differences in Stem Cell Organization.International journal of molecular sciences · 2025Article
- Investigating the interplay between mitophagy and diabetic neuropathy: Uncovering the hidden secrets of the disease pathology.Pharmacological research · 2024Review
- Exploring cell competition for the prevention and therapy of esophageal squamous cell carcinoma.Biochemical pharmacology · 2023Review
- The Molecular Characterization of Genetic Abnormalities in Esophageal Squamous Cell Carcinoma May Foster the Development of Targeted Therapies.Current oncology (Toronto, Ont.) · 2023Review
- NRF2 Controls the Competitive Fitness of Squamous Epithelial Cells in the Mouse Esophagus.Cellular and molecular gastroenterology and hepatology · 2023Article
- The KEAP1-NRF2 System and Esophageal Cancer.Cancers · 2022Review
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND &
aimsNF-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.
methodsWe 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.
resultsKEAP1-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.
conclusionsConstitutive 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.
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