MiR 21 is an EGFR regulated anti apoptotic factor in lung cancer in never smokers
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.
Proceedings of the National Academy of Sciences