Abstract
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.
Highlights
Lung cancer, predominantly non–small cell lung cancer (NSCLC), remains the leading cause of cancer death worldwide [1]
Growth arrest and enlarged cell size were observed in epidermal growth factor receptor (EGFR)-silenced CL1-5 cells (Supplementary Fig. S1A), whereas quantitative reverse transcription-PCR and immunoblotting showed that both EGFR mRNA and protein levels were significantly downregulated (Fig. 1A). miRNA microarray analysis of total RNA from EGFR-silenced cells was used to identify miRNAs regulated by EGFR, and among them, miR-7 showed a significant downregulation (Table 1)
Knockdown of EGFR inhibited the expression of miR-7 in A549 lung cancer cells, both EGFR and miR-7 expressions were lower in A549 cells than in CL1-5 cells (Supplementary Fig. S1B)
Summary
Predominantly non–small cell lung cancer (NSCLC), remains the leading cause of cancer death worldwide [1]. EGFR is overexpressed or mutated in most NSCLC cases, and deregulated expression of EGFR together with ligand binding and con-. Authors' Affiliations: 1Institute of Biomedical Sciences and 2NRPGM Core Facilities for Proteomics and Glycomcis and Institute of Biological Chemistry, Academia Sinica; 3Department of Thoracic Surgery, 4Center of Excellence for Cancer Research and School of Public Health, and 5Department of Urology, Taipei Medical University Hospital; 6National Yang-Ming University, Taipei, Taiwan; 7Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; and 8Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
