Journal Article

Regulation of Epidermal Growth Factor Receptor Signaling and Erlotinib Sensitivity in Head and Neck Cancer Cells by miR-7

Kalinowski, Felicity C., Epis, Michael R., Ali, Alishum, Candy, Patrick A., Webster, Rebecca J., Leedman, Peter J., Giles, Keith M., Ganda, Clarissa

2012

Overview

Elevated expression and activity of the epidermal growth factor receptor (EGFR)/protein kinase B (Akt) signaling pathway is associated with development, progression and treatment resistance of head and neck cancer (HNC). Several studies have demonstrated that microRNA-7 (miR-7) regulates EGFR expression and Akt activity in a range of cancer cell types via its specific interaction with the EGFR mRNA 3'-untranslated region (3'-UTR). In the present study, we found that miR-7 regulated EGFR expression and Akt activity in HNC cell lines, and that this was associated with reduced growth in vitro and in vivo of cells (HN5) that were sensitive to the EGFR tyrosine kinase inhibitor (TKI) erlotinib (Tarceva). miR-7 acted synergistically with erlotinib to inhibit growth of erlotinib-resistant FaDu cells, an effect associated with increased inhibition of Akt activity. Microarray analysis of HN5 and FaDu cell lines transfected with miR-7 identified a common set of downregulated miR-7 target genes, providing insight into the tumor suppressor function of miR-7. Furthermore, we identified several target miR-7 mRNAs with a putative role in the sensitization of FaDu cells to erlotinib. Together, these data support the coordinate regulation of Akt signaling by miR-7 in HNC cells and suggest the therapeutic potential of miR-7 alone or in combination with EGFR TKIs in this disease.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 3' Untranslated Regions / AKT protein / Analysis / Apoptosis / Biology / Biotechnology / Breast cancer / Cancer / Cancer research / Cancer therapies / Cell cycle / Cell growth / Cell Line, Tumor / DNA microarrays / Enzyme inhibitors / Epidermal growth factor / Epidermal growth factor receptors / Epidermal growth factors / ErbB Receptors - genetics / ErbB Receptors - metabolism / Erlotinib / Erlotinib Hydrochloride / Gene expression / Genes / Head & neck cancer / Head and neck cancer / Head and Neck Neoplasms - pathology / Humans / Inhibitor drugs / Insulin-like growth factors / Kinases / Laboratories / Medical prognosis / Medical research / Medicine / Metastasis / MicroRNA / MicroRNAs / MicroRNAs - physiology / miRNA / mRNA / Mutation / Oligonucleotide Array Sequence Analysis / Prostate cancer / Protein Kinase Inhibitors - pharmacology / Protein-tyrosine kinase / Proto-Oncogene Proteins c-akt - metabolism / Quinazolines - pharmacology / Ribonucleic acid / RNA / RNA, Messenger - genetics / Rodents / Signal Transduction / Signaling / Studies / Target recognition / Targeted cancer therapy / Treatment resistance / Tumor suppressor genes / Tyrosine