Journal Article

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

Seike, Masahiro, Horikawa, Izumi, Mathe, Ewy A, Kudoh, Shoji, Schetter, Aaron J, Bowman, Elise D, Harris, Curtis C, Sugimura, Haruhiko, Yang, Ping, Croce, Carlo M, Goto, Akiteru, Okano, Tetsuya, Jen, Jin, Gemma, Akihiko

2009

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adenocarcinoma / Adult / Aged / Apoptosis / Apoptosis - drug effects / Biological Sciences / Cancer / Carcinogenesis / Carcinoma, Non-Small-Cell Lung - enzymology / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Cell Line, Tumor / Cell lines / epidermal growth factor receptors / Female / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - drug effects / genes / Genetic mutation / Humans / Lung cancer / Lung neoplasms / Lung Neoplasms - enzymology / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Lungs / Male / MicroRNA / MicroRNAs - genetics / MicroRNAs - metabolism / Middle Aged / mutants / Mutation / Mutation - genetics / neoplasm cells / Quinazolines / Receptor, Epidermal Growth Factor - genetics / Receptor, Epidermal Growth Factor - metabolism / Ribonucleic acid / RNA / RNA, Antisense - pharmacology / signal transduction / Signal Transduction - drug effects / Smoking / Smoking - pathology / Tobacco smoking / Tumors / Tyrphostins - pharmacology