Nrf2 and Keap1 abnormalities in esophageal squamous cell carcinoma and association with the effect of chemoradiotherapy

Thorac Cancer. 2018 Jun;9(6):726-735. doi: 10.1111/1759-7714.12640. Epub 2018 Apr 19.


Background: The Keap1-Nrf2 pathway is a key antioxidant and redox signaling cascade. Pathway abnormalities enhance the reactive oxygen species scavenging ability of cancer cells; thus the pathway is involved in carcinogenesis and resistance to chemoradiotherapy (CRT). This retrospective study was conducted to examine the status of the Keap1-Nrf2 pathway in locally advanced esophageal squamous cell carcinoma (ESCC) and to analyze its prognostic value in patients receiving CRT.

Methods: Nrf2 and Keap1 expression were immunohistochemically examined in 152 ESCC and 31 normal esophageal mucosae. All ESCC specimens were obtained from patients with locally advanced ESCC who underwent CRT.

Results: Strong staining of nuclear and cytoplasmic Nrf2 and limited or absent Keap1 expression was uncommon in normal tissues, but frequently observed in ESCC. Interaction between Nrf2 and Keap1 in normal mucosae is negatively correlated, while in tumors there is no negative correlation, indicating that there is little to no interaction between Nrf2 and Keap1 in ESCC. Positive Nrf2 expression in the nucleus was of diagnostic value for predicting ESCC from normal esophageal mucosae, and was significantly associated with poorer clinical response and poor progression-free survival after CRT. The value of Keap1 expression for diagnosis and predicting CRT outcomes was marginal. These different influences of Keap1 and Nrf2 on ESCC indicated that the signaling of this pathway was disturbed and displayed a Keap1-independent pattern.

Conclusion: Aberrant signaling via the Keap1-Nrf2 pathway was common in ESCC and was associated with response and survival after CRT.

Keywords: Chemoradiotherapy; Keap1/Nrf2; esophageal squamous cell carcinoma; locally advanced.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / metabolism
  • Chemoradiotherapy*
  • Esophageal Neoplasms / mortality
  • Esophageal Neoplasms / therapy*
  • Esophageal Squamous Cell Carcinoma / mortality
  • Esophageal Squamous Cell Carcinoma / therapy*
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Male
  • Middle Aged
  • Mucous Membrane / metabolism
  • NF-E2-Related Factor 2 / metabolism*
  • Prognosis
  • Retrospective Studies
  • Treatment Outcome


  • Biomarkers, Tumor
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human