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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)12085-12090
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number29
DOIs
StatePublished - Jul 21 2009
Externally publishedYes

Keywords

  • Apoptosis
  • EGFR-TKI
  • Microarray
  • MicroRNA
  • Therapeutic target

ASJC Scopus subject areas

  • General

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