Abstract
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.
Highlights
Head and neck cancer (HNC) is the sixth most common cancer, with approximately 600,000 new cases globally per annum [1]
HN5 cells are representative of epidermal growth factor receptor (EGFR) inhibitor-sensitive HNC, FaDu cells represent HNC that is resistant to EGFR inhibition, and SCC-25 cells represent HNC with intermediate EGFR-inhibitor resistance
Given the important role of EGFR signaling in HNC tumorigenesis and treatment, we investigated the capacity of miR-7 to inhibit EGFR expression and downstream signaling in HNC cell lines
Summary
Head and neck cancer (HNC) is the sixth most common cancer, with approximately 600,000 new cases globally per annum [1]. The epidermal growth factor receptor (EGFR), a member of the ErbB receptor tyrosine kinase (RTK) family, is overexpressed in greater than 80% of all HNCs and is an independent predictor of poor outcome [3]. Clinical trials in HNC evaluating the combination of EGFR inhibitors with other therapeutic approaches have been initiated, as well as studies investigating new generation anti-EGFR agents, such as the antiEGFR mAb panitumumab and the dual EGFR/HER2 TKI lapatinib [12]. The poor clinical response of HNC to anti-EGFR therapies is due to the inherent and acquired resistance of HNC cells to these agents, which is thought to occur via several mechanisms, including mutations within EGFR and its downstream effectors that activate signaling
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