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.