Regulation of Epidermal Growth Factor Receptor Signaling in Human Cancer Cells by MicroRNA-7

Karina J. Price,Rebecca J. Webster,John S. Mattick,Peter J. Leedman,Keith M. Giles,Priscilla M. Zhang

doi:10.1074/jbc.m804280200

Abstract

The epidermal growth factor receptor (EGFR) is frequently overexpressed in cancer and is an important therapeutic target. Aberrant expression and function of microRNAs have been associated with tumorigenesis. Bioinformatic predictions suggest that the human EGFR mRNA 3'-untranslated region contains three microRNA-7 (miR-7) target sites, which are not conserved across mammals. We found that miR-7 down-regulates EGFR mRNA and protein expression in cancer cell lines (lung, breast, and glioblastoma) via two of the three sites, inducing cell cycle arrest and cell death. Because miR-7 was shown to decrease EGFR mRNA expression, we used microarray analysis to identify additional mRNA targets of miR-7. These included Raf1 and multiple other genes involved in EGFR signaling and tumorigenesis. Furthermore, miR-7 attenuated activation of protein kinase B (Akt) and extracellular signal-regulated kinase 1/2, two critical effectors of EGFR signaling, in different cancer cell lines. These data establish an important role for miR-7 in controlling mRNA expression and indicate that miR-7 has the ability to coordinately regulate EGFR signaling in multiple human cancer cell types.

Highlights

The epidermal growth factor receptor (EGFR),4 a member of the erbB receptor family, is widely expressed in human tissues and regulates important cellular processes, including proliferation, differentiation, and development [1]
MicroRNAs are short, endogenous, non-coding RNA molecules that bind with imperfect complementarity to the 3Ј-untranslated regions (3Ј-UTRs) of target mRNAs, causing translational repression of the target gene or degradation of the target mRNA [5,6,7]. miRNAs are involved in a range of processes that includes development, differentiation [8], proliferation, and apoptosis [9] and have been implicated in cancer [10]
We demonstrate the potential for miR-7 to act as a tumor suppressor by coordinately regulating the EGFR signaling pathway at multiple levels to repress protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) activity in human cancer cell lines

Summary

Introduction

The epidermal growth factor receptor (EGFR),4 a member of the erbB receptor family, is widely expressed in human tissues and regulates important cellular processes, including proliferation, differentiation, and development [1]. We demonstrate the potential for miR-7 to act as a tumor suppressor by coordinately regulating the EGFR signaling pathway at multiple levels to repress protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) activity in human cancer cell lines.

Results

Conclusion