期刊
ONCOGENE
卷 41, 期 25, 页码 3423-3432出版社
SPRINGERNATURE
DOI: 10.1038/s41388-022-02348-0
关键词
-
资金
- National Institutes of Environmental and Health Sciences [T32ES007126]
- Golberg
- National Cancer Institute [CA216051]
- UNC Lineberger Clinical/Translational Research Award
- [5R01CA244841-02]
- [5U01CA231844-04]
- [5U24CA213274-05]
This study demonstrates the prevalence of Nrf2 (E79Q/+) mutation in human tumors, and suggests a role for NRF2 activation in the development of small cell lung cancer (SCLC).
Studies have shown that Nrf2(E79Q/+) is one of the most common mutations found in human tumors. To elucidate how this genetic change contributes to lung cancer, we compared lung tumor development in a genetically-engineered mouse model (GEMM) with dual Trp53/p16 loss, the most common mutations found in human lung tumors, in the presence or absence of Nrf2(E79Q/+). Trp53/p16-deficient mice developed combined-small cell lung cancer (C-SCLC), a mixture of pure-SCLC (P-SCLC) and large cell neuroendocrine carcinoma. Mice possessing the LSL-Nrf2(E79Q) mutation showed no difference in the incidence or latency of C-SCLC compared with Nrf2(+/+) mice. However, these tumors did not express NRF2 despite Cre-induced recombination of the LSL-Nrf2(E79Q) allele. Trp53/p16-deficient mice also developed P-SCLC, where activation of the NRF2(E79Q) mutation associated with a higher incidence of this tumor type. All C-SCLCs and P-SCLCs were positive for NE-markers, NKX1-2 (a lung cancer marker) and negative for P63 (a squamous cell marker), while only P-SCLC expressed NRF2 by immunohistochemistry. Analysis of a consensus NRF2 pathway signature in human NE+-lung tumors showed variable activation of NRF2 signaling. Our study characterizes the first GEMM that develops C-SCLC, a poorly-studied human cancer and implicates a role for NRF2 activation in SCLC development.
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