MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers.

Abstract

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.

• Authors: Masahiro Seike, Akiteru Goto, Tetsuya Okano, Elise D Bowman, Aaron J Schetter, Izumi Horikawa, Ewy A Mathe, Jin Jen, Ping Yang, Haruhiko Sugimura, Akihiko Gemma, Shoji Kudoh, Carlo M Croce, Curtis C Harris
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 29 Pg. 12085-90 (Jul 21 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19597153 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• MIRN21 microRNA, human
• MicroRNAs
• Quinazolines
• RNA, Antisense
• Tyrphostins
• RTKI cpd
• ErbB Receptors

Topics

• Adult
• Aged
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (enzymology, genetics, pathology)
• Cell Line, Tumor
• ErbB Receptors (genetics, metabolism)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (enzymology, genetics, pathology)
• Male
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Mutation (genetics)
• Quinazolines
• RNA, Antisense (pharmacology)
• Signal Transduction (drug effects)
• Smoking (pathology)
• Tyrphostins (pharmacology)