EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF.
MicroRNAs (miRNA) mediate distinct gene regulatory pathways triggered by epidermal growth factor receptor (EGFR) activation, which occurs commonly in lung cancers with poor prognosis. In this study, we report the discovery and mechanistic characterization of the miRNA miR-7 as an oncogenic "oncomiR" and its role as a key mediator of EGFR signaling in lung cancer cells. EGFR activation or ectopic expression of Ras as well as c-Myc stimulated miR-7 expression in an extracellular signal-regulated kinase (ERK)-dependent manner, suggesting that EGFR induces miR-7 expression through a Ras/ERK/Myc pathway. In support of this likelihood, c-Myc bound to the miR-7 promoter and enhanced its activity. Ectopic miR-7 promoted cell growth and tumor formation in lung cancer cells, significantly increasing the mortality of nude mice hosts, which were orthotopically implanted with lung cancers. Quantitative proteomic analysis revealed that miR-7 decreased levels of the Ets2 transcriptional repression factor ERF, the coding sequence of which was found to contain a miR-7 complementary sequence. Indeed, ectopic miR-7 inhibited production of ERF messages with a wild-type but not a silently mutated coding sequence, and ectopic miR-7 rescued growth arrest produced by wild-type but not mutated ERF. Together, these results identified that ERF is a direct target of miR-7 in lung cancer. Our findings suggest that miR-7 may act as an important modulator of EGFR-mediated oncogenesis, with potential applications as a novel prognostic biomarker and therapeutic target in lung cancer.
Chou
Yu-Ting
YT
Institute of Biomedical Sciences and NRPGM Core Facilities for Proteomics and Glycomcis and Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
Lin
Hua-Heng
HH
Lien
Yung-Chang
YC
Wang
Yuan-Hung
YH
Hong
Chun-Fu
CF
Kao
Yu-Rung
YR
Lin
Sheng-Chieh
SC
Chang
Ying-Che
YC
Lin
Shu-Yu
SY
Chen
Shu-Jen
SJ
Chen
Hua-Chien
HC
Yeh
Shauh-Der
SD
Wu
Cheng-Wen
CW
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012097:Repressor Proteins; D018631:ras Proteins; C107465:ERF protein, human; C549242:MIRN7-1 microRNA, human; C489427:MYC protein, human; C512478:EGFR protein, human