NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer
Open accessAbstract
Esophageal squamous cancer (ESC) is one of the most aggressive tumors of the gastrointestinal tract. A combination of chemotherapy and radiation therapy (CRT) has improved the clinical outcome, but the molecular background determining the effectiveness of therapy remains unknown. NRF2 is a master transcriptional regulator of stress adaptation, and gain of-function mutation of NRF2 in cancer confers resistance to stressors including anticancer therapy. Direct resequencing analysis revealed that Nrf2 gain-of-function mutation occurred recurrently (18/82, 22%) in advanced ESC tumors and ESC cell lines (3/10). The presence of Nrf2 mutation was associated with tumor recurrence and poor prognosis. Short hairpin RNA-mediated down-regulation of NRF2 in ESC cells that harbor only mutated Nrf2 allele revealed that themutant NRF2 conferred increased cell proliferation, attachment-independent survival, and resistance to 5-fluorouracil and γ-irradiation. Based on the Nrf2 mutation status, gene expression signatures associated with NRF2 mutation were extracted from ESC cell lines, and their potential utility for monitoring and prognosis was examined in a cohort of 33 pre-CRT cases of ESC. The molecular signatures of NRF2 mutation were significantly predictive and prognostic for CRT response. In conclusion, recurrent NRF2 mutation confers malignant potential and resistance to therapy in advanced ESC, resulting in a poorer outcome. Molecular signatures of NRF2 mutation can be applied as predictive markers of response to CRT, and efficient inhibition of aberrant NRF2 activation could be a promising approach in combination with CRT.
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Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance.
“Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, thereby leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance (e.g., chemoresistance) (Figure 8) [161,162,163,164,165,166,167,168,169,170,171].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [161]
Upregulation of Nrf2-mediated antioxidant proteins renders cancer cells resistant to chemotherapeutic drugs (e.g., cisplatin, 5-fluorouracil, docetaxel, and bortezomib) and radiotherapy.
“The resultant upregulation of Nrf2-mediated antioxidant proteins renders cancer cells resistant to chemotherapeutic drugs (e.g., cisplatin, 5-fluorouracil, docetaxel, and bortezomib) and radiotherapy [47,161,165,178,179,180,181,182,183,184].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [161]
Aberrant Nrf2 expression and poor prognosis have been revealed in a wide range of cancers, including lung, esophageal, breast, bladder, liver, prostate, and colorectal carcinomas.
“numerous studies have revealed aberrant Nrf2 expression and poor prognosis in a wide range of cancers, including, among others, lung, esophageal, breast, bladder, liver, prostate, and colorectal carcinomas [161,162,169,170,171,173,174]”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [161]
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- Authors
- Shibata, T., Kokubu, A., Saito, S., Narisawa-Saito, M., Sasaki, H., Aoyagi, K., Yoshimatsu, Y., Tachimori, Y., Kushima, R., Kiyono, T., & Yamamoto, M.
- Affiliations
- National Cancer Center Hospital (JP)
- National Cancer Center Research Institute (JP)
- Tohoku University (JP)
- Corresponding author
- Shibata, Tatsuhiro
- ORCID
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 13
- Issue
- 9
- Pages
- 864-IN26
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC3182278
- OpenAlex
- W1850426716
- Cited by
- 224
- References
- 41
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 13 · 2023: 12 · 2022: 21 · 2021: 20 · 2020: 27 · 2019: 12 · 2018: 18 · 2017: 23 · 2016: 15 · 2015: 12 · 2014: 9 · 2013: 17 · 2012: 6
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Princess Takamatsu Cancer Research Fund
- Japan Society for the Promotion of Science (19GS0312)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Surgery › Esophageal Cancer Research and Treatment
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Keywords
- NRF2 mutation, esophageal squamous cell carcinoma, chemoradiotherapy resistance, gain-of-function mutations, tumor recurrence, prognostic factors, predictive biomarkers, 5-fluorouracil resistance, gamma irradiation resistance, gene expression signatures, Nrf2 inhibition, cell proliferation, stress adaptation
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Base Sequence, Carcinoma, Squamous Cell, Cell Adhesion, Esophageal Neoplasms, Female, Fluorouracil, Gamma Rays, Humans, Male, Mutation, Neoplasm Recurrence, Local, Prognosis, Radiation Tolerance, Biomarkers, Tumor, Down-Regulation, Treatment Outcome, Sequence Analysis, DNA, Drug Resistance, Neoplasm, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, NF-E2-Related Factor 2, Chemoradiotherapy
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