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.
Seike
Masahiro
M
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Goto
Akiteru
A
Okano
Tetsuya
T
Bowman
Elise D
ED
Schetter
Aaron J
AJ
Horikawa
Izumi
I
Mathe
Ewy A
EA
Jen
Jin
J
Yang
Ping
P
Sugimura
Haruhiko
H
Gemma
Akihiko
A
Kudoh
Shoji
S
Croce
Carlo M
CM
Harris
Curtis C
CC
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011799:Quinazolines; D016372:RNA, Antisense / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000473:pathology*; D020032:Tyrphostins / Q000494:pharmacology
C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D011799:Quinazolines; D016372:RNA, Antisense; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors