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Cellular Nrf2 Levels Determine Cell Fate during Chemical Carcinogenesis in Esophageal Epithelium

Makoto Horiuchi1,2, Keiko Taguchi1,3,4, Wataru Hirose1,2

  • 1Department of Medical Biochemistry, Tohoku University, Sendai, Japan.

Molecular and Cellular Biology
|December 1, 2020
PubMed

Insights

Nrf2-deficient cells are eliminated when exposed to carcinogens, preventing cancer. This shows that Nrf2

Area of Science:

  • Oncology
  • Molecular Biology
  • Carcinogenesis

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is crucial for cellular defense against carcinogens.
  • Previous studies using systemic Nrf2 knockout mice indicated Nrf2-deficient cells are susceptible to carcinogens and cancer development.
  • The oncogenic potential of Nrf2-deficient epithelial cells within a normal cellular environment, particularly in the esophagus, remained unclear.

Purpose of the Study:

  • To investigate the fate and oncogenic potential of Nrf2-deficient esophageal epithelial cells in a mixed cellular environment.
  • To assess the role of Nrf2 in 4-nitroquinoline-1-oxide (4NQO)-induced carcinogenesis in the esophageal epithelium.

Main Methods:

  • Generation of a novel mouse model with inducible Cre-mediated deletion of Nrf2 in adult esophageal basal epithelial cells.
  • Utilizing tamoxifen to induce recombination, creating mice with approximately equal levels of Nrf2-deleted and Nrf2-intact cells.
  • Exposure of the mouse model to the carcinogen 4-nitroquinoline-1-oxide (4NQO) and monitoring tumor development.

Main Results:

  • Nrf2-deleted epithelial cells were stable for 12 weeks under unstressed conditions.
  • Upon 4NQO exposure, Nrf2-deleted cells accumulated DNA damage and were selectively eliminated from the epithelium.
  • The vast majority of 4NQO-induced tumors originated from Nrf2-intact cells, not Nrf2-deleted cells.

Conclusions:

  • Nrf2-deficient esophageal epithelial cells do not undergo carcinogenesis due to selective elimination following carcinogen exposure.
  • Cellular Nrf2 levels and the surrounding epithelial microenvironment are critical determinants of cell fate and oncogenic potential in 4NQO-induced carcinogenesis.
Keywords:
4NQONrf2carcinogenesiscell competitionesophagus

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