MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers
Open accessAbstract
Fifteen percent of lung cancer cases occur in never-smokers and show characteristics that are molecularly and clinically distinct from those in smokers. Epidermal growth factor receptor ( EGFR ) gene mutations, which are correlated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), are more frequent in never-smoker lung cancers. In this study, microRNA (miRNA) expression profiling of 28 cases of never-smoker lung cancer identified aberrantly expressed miRNAs, which were much fewer than in lung cancers of smokers and included miRNAs previously identified (e.g., up-regulated miR-21) and unidentified (e.g., down-regulated miR-138) in those smoker cases. The changes in expression of some of these miRNAs, including miR-21, were more remarkable in cases with EGFR mutations than in those without these mutations. A significant correlation between phosphorylated-EGFR ( p -EGFR) and miR-21 levels in lung carcinoma cell lines and the suppression of miR-21 by an EGFR-TKI, AG1478, suggest that the EGFR signaling is a pathway positively regulating miR-21 expression. In the never-smoker–derived lung adenocarcinoma cell line H3255 with mutant EGFR and high levels of p -EGFR and miR-21, antisense inhibition of miR-21 enhanced AG1478-induced apoptosis. In a never-smoker–derived adenocarcinoma cell line H441 with wild-type EGFR , the antisense miR-21 not only showed the additive effect with AG1478 but also induced apoptosis by itself. These results suggest that aberrantly increased expression of miR-21, which is enhanced further by the activated EGFR signaling pathway, plays a significant role in lung carcinogenesis in never-smokers, as well as in smokers, and is a potential therapeutic target in both EGFR -mutant and wild-type cases.
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EGFR and HER2/neu signaling positively regulates miR-21 expression in human lung and breast carcinoma cell lines, respectively.
“As well, epidermal growth factor receptor (EGFR) and HER2/neu signaling positively regulates miR-21 expression in human lung and breast carcinoma cell lines, respectively (Huang et al., 2009; Seike et al., 2009).”
From Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21 (2010) · cites this paper as Seike et al., 2009
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- Authors
- Seike, M., Goto, A., Okano, T., Bowman, E. D., Schetter, A. J., Horikawa, I., Mathe, E. A., Jen, J., Yang, P., Sugimura, H., Gemma, A., Kudoh, S., Croce, C. M., & Harris, C. C.
- Affiliations
- National Institutes of Health (US)
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
- Mayo Clinic (US)
- Hamamatsu University School of Medicine (JP)
- Nippon Medical School (JP)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-07-21
- Volume
- 106
- Issue
- 29
- Pages
- 12085-12090
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2715493
- OpenAlex
- W2037011799
- Cited by
- 500
- References
- 5
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 9 · 2023: 13 · 2022: 18 · 2021: 19 · 2020: 18 · 2019: 21 · 2018: 30 · 2017: 22 · 2016: 39 · 2015: 35 · 2014: 56 · 2013: 58 · 2012: 55
- FWCI
- 17.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Japan Society for the Promotion of Science (21591006)
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- miR-21, EGFR mutation, never-smoker lung cancer, lung adenocarcinoma, EGFR signaling, EGFR tyrosine kinase inhibitors, AG1478, EGFR phosphorylation, miR-138, miRNA expression profiling, apoptosis, lung carcinogenesis, therapeutic target
- MeSH terms
- Adult, Aged, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Quinazolines, Smoking, Signal Transduction, Gene Expression Regulation, Neoplastic, RNA, Antisense, Apoptosis, Tyrphostins, Gene Expression Profiling, MicroRNAs, Cell Line, Tumor, ErbB Receptors
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