EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF

Yu Ting Chou, Hua Heng Lin, Yung Chang Lien, Yuan Hung Wang, Chun Fu Hong, Yu Rung Kao, Sheng Chieh Lin, Ying Che Chang, Shu Yu Lin, Shu Jen Chen, Hua Chien Chen, Shauh Der Yeh, Cheng Wen Wu

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190 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)8822-8831
Number of pages10
JournalCancer Research
Volume70
Issue number21
DOIs
Publication statusPublished - Nov 1 2010

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Chou, Y. T., Lin, H. H., Lien, Y. C., Wang, Y. H., Hong, C. F., Kao, Y. R., Lin, S. C., Chang, Y. C., Lin, S. Y., Chen, S. J., Chen, H. C., Yeh, S. D., & Wu, C. W. (2010). EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF. Cancer Research, 70(21), 8822-8831. https://doi.org/10.1158/0008-5472.CAN-10-0638