title: Regulation of epidermal growth factor receptor signaling and erlotinib sensitivity in head and neck cancer cells by miR-7.
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.
authors.affiliation: Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and University of Western Australia Centre for Medical Research, Perth, Western Australia, Australia.
authors.forename: Felicity C
authors.initials: FC
authors.lastname: Kalinowski
authors.forename: Keith M
authors.initials: KM
authors.lastname: Giles
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Candy
authors.forename: Alishum
authors.initials: A
authors.lastname: Ali
authors.forename: Clarissa
authors.initials: C
authors.lastname: Ganda
authors.forename: Michael R
authors.initials: MR
authors.lastname: Epis
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Webster
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Leedman
mesh_terms: D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D012333:RNA, Messenger; C549242:MIRN7-1 microRNA, human