Coordinated targeting of the EGFR signaling axis by MicroRNA-27a*

Xiaoli Wu, Mihir K. Bhayani, Cristina T. Dodge, Milena S. Nicoloso, Yunyun Chen, Xiaofeng Yan, Makoto Adachi, Ligy Thomas, Chad E. Galer, Tilahun Jiffar, Curtis R. Pickering, Michael E. Kupferman, Jeffrey N. Myers, George A. Calin, Stephen Y. Lai

Research output: Contribution to journalArticle

Abstract

Epidermal growth factor receptor (EGFR) has been characterized as a critical factor in the development and progression of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC). However, monotherapy with EGFR-specific agents has not been as dramatic as preclinical studies have suggested. Since complex regulation of the EGFR signaling axis might confound current attempts to inhibit EGFR directly, we searched for microRNAs (miRNAs) that may target the EGFR signaling axis. We identified miR-27a (miR-27a-3p) and its complementary or star (*) strand, miR-27a* (miR-27a-5p), as novel miRNAs targeting EGFR, which were significantly downregulated in multiple HNSCC cell lines. Analysis of human specimens demonstrated that miR-27a* is significantly underexpressed in HNSCC as compared to normal mucosa. Increased expression of miR-27a* in HNSCC produced a profound cytotoxic effect not seen with miR-27a. Analysis for potential targets of miR-27a* led to the identification of AKT1 (protein kinase B) and mTOR (mammalian target of rapamycin) within the EGFR signaling axis. Treatment with miR-27a* led to coordinated downregulation of EGFR, AKT1 and mTOR. Overexpression of EGFR signaling pathway components decreased the overall effect of miR-27a* on HNSCC cell viability. Constitutive and inducible expression of miR-27a* in a murine orthotopic xenograft model of oral cavity cancer led to decreased tumor growth. Direct intratumoral injection of miR-27a* inhibited tumor growth in vivo. These findings identify miR-27a* as a functional star sequence that exhibits novel coordinated regulation of the EGFR pathway in solid tumors and potentially represents a novel therapeutic option.

Original languageEnglish
Pages (from-to)1388-1398
Number of pages11
JournalOncotarget
Volume4
Issue number9
Publication statusPublished - 2013

Keywords

  • AKT1
  • EGFR
  • miRNA
  • miRNA-27a*
  • miRNA-27a-5p
  • mTOR

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Wu, X., Bhayani, M. K., Dodge, C. T., Nicoloso, M. S., Chen, Y., Yan, X., Adachi, M., Thomas, L., Galer, C. E., Jiffar, T., Pickering, C. R., Kupferman, M. E., Myers, J. N., Calin, G. A., & Lai, S. Y. (2013). Coordinated targeting of the EGFR signaling axis by MicroRNA-27a*. Oncotarget, 4(9), 1388-1398.