NRF2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates the expression of many cytoprotective genes. NRF2 activation is mainly regulated by KEAP1 (kelch-like ECH-associated protein 1) through ubiquitination and proteasome degradation. Esophageal cancer is classified histologically into two major types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC harbors more genetic alterations in the KEAP-NRF2 system than EAC does, which results in NRF2 activation in these cancers. NRF2-addicted ESCC exhibits increased malignancy and acquisition of resistance to chemoradiotherapy. Therefore, it has been recognized that the development of drugs targeting the KEAP1-NRF2 system based on the molecular dissection of NRF2 function is important and urgent for the treatment of ESCC, along with efficient clinical screening for NRF2-addicted ESCC patients. Recently, the fate of NRF2-activated cells in esophageal tissues, which was under the influence of strong cell competition, and its relationship to the pathogenesis of ESCC, was clarified. In this review, we will summarize the current knowledge of the KEAP1-NRF2 system and the treatment of ESCC. We propose three main strategies for the treatment of NRF2-addicted cancer: (1) NRF2 inhibitors, (2) synthetic lethal drugs for NRF2-addicted cancers, and (3) NRF2 inducers of the host defense system.
Nrf2 is essential for cytoprotection against carcinogens, and through systemic Nrf2-knockout mice, Nrf2-deficient cells were shown to be susceptible to chemical carcinogens and prone to developing cancers. However, the oncogenic potential of Nrf2-deficient epithelial cells surrounded by normal cells in the esophagus could not be assessed by previous models, and the fate of Nrf2-deficient cells in such situations remains elusive. In this study, therefore, we generated mice that harbor almost equal levels of Nrf2-deficient and Nrf2-intact cells in the basal layer of the esophageal epithelium utilizing inducible Cre-mediated recombination of Nrf2 alleles in adults through moderate use of tamoxifen. In this mouse model, Nrf2-deleted epithelial cells were maintained with no obvious decrease or phenotypic changes for 12 weeks under unstressed conditions. Upon exposure to the carcinogen 4-nitroquinoline-1-oxide (4NQO), the Nrf2-deleted cells accumulated DNA damage and selectively disappeared from the epithelium, so almost all 4NQO-induced tumors originated from Nrf2-intact cells and not from Nrf2-deleted cells. We propose that Nrf2-deleted cells do not undergo carcinogenesis due to selective elimination upon exposure to 4NQO, indicating that cellular Nrf2 abundance and the epithelial environment determine the cell fate or oncogenic potential of esophageal epithelial cells in 4NQO-induced carcinogenesis.
Highlights
We report a case of esophageal cancer treated with PDT followed by esophagectomy.
We assessed the PDT effect on adjacent tissues based on surgery and pathology.
PDT can cause intense inflammation in tissues adjacent to the tumor.
The location should be considered when performing salvage esophagectomy after PDT.
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