Coordinated Targeting of the EGFR Signaling Axis by MicroRNA-27a*
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Xiaoli Wu1,2,*, Mihir K. Bhayani1,*, Cristina T. Dodge1, Milena S. Nicoloso3, Yunyun Chen1, Xiaofeng Yan1, Makoto Adachi1, Ligy Thomas1, Chad E. Galer4, Tilahun Jiffar1, Curtis R. Pickering1, Michael E. Kupferman1, Jeffrey N. Myers1, George A. Calin3, Stephen Y. Lai1,5
1 Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
2 Division of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
3 Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
4 Department of Otolaryngology, University of Indiana School of Medicine, Indianapolis, IN, USA
5 Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
* These authors contributed equally to this work.
Stephen Y. Lai, email:
Keywords: miRNA EGFR AKT1 mTOR miRNA-27a* miRNA-27a-5p
Received: July 29, 2013 Accepted: August 4, 2013 Published: August 6, 2013
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.
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