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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. Differential gene expression in head and neck cancer cell lines HN5 and FaDu under conditions of 24 h miR-NC (negative control) vs. miR-7 treatment.

ORGANISM(S): Homo sapiens

SUBMITTER: Patrick Candy

PROVIDER: E-GEOD-40130 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Regulation of epidermal growth factor receptor signaling and erlotinib sensitivity in head and neck cancer cells by miR-7

Project description: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.

2012-08-16 | GSE40130 | GEO

Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib

Project description:Elevated expression and activity of the epidermal growth factor receptor (EGFR) is associated with development and progression of head and neck cancer (HNC) and a poor prognosis. Clinical trials with EGFR tyrosine kinase inhibitors (TKIs; eg. erlotinib) have been disappointing in HNC. To investigate the mechanisms mediating resistance to these agents, we developed a HNC cell line (HN5-ER) with acquired erlotinib resistance. In contrast to parental HN5 HNC cells, HN5-ER cells exhibited an epithelial-mesenchymal (EMT) phenotype with increased migratory potential, reduced E-cadherin and epithelial-associated miRNAs, and elevated vimentin expression. Phosphorylated RTK profiling identified Axl activation in HN5-ER cells. Growth and migration of HN5-ER cells was blocked with a specific Axl inhibitor, R428, and R428 re-sensitized HN5-ER cells to erlotinib. Microarray analysis of HN5-ER cells confirmed the EMT phenotype associated with acquired erlotinib resistance, and identified activation of gene expression associated with cell migration and inflammation pathways. Moreover, increased expression and secretion of interleukin (IL)-6 and IL-8 in HN5-ER cells suggested a role for inflammatory cytokine signaling in EMT and erlotinib resistance. Expression of the tumor suppressor miR-34a was reduced in HN5-ER cells and increasing its expression abrogated Axl expression and reversed erlotinib resistance. Finally, analysis of 302 HNC patients revealed that high tumor Axl mRNA expression was associated with poorer survival (HR 1.66, p=0.007). In summary, our results identify Axl as a key mediator of acquired erlotinib resistance in HNC and suggest that therapeutic inhibition of Axl by small molecule drugs or specific miRNAs might overcome anti-EGFR therapy resistance. Differential gene expression between parental and acquired erlotinib resistant head and neck cancer cell lines of HN5.

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Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib

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Genome-wide analysis of EGFR inhibitor erlotinib treatment in Head and neck, squamous cell carcinoma's FADU, SQ20B and Cal 27

Project description:Chronic inflammation plays a significant role in tumor promotion, migration and invasion. Using microarray analysis, we observed a profound increase in genes involved in pro-inflammatory pathways in epidermal growth factor receptor inhibitor (EGFRI)-treated head and neck squamous cell carcinoma (HNSCC) cell lines compared to their respective vehicle-treated cell lines. We hypothesized that the efficacy of EGFRIs may be offset by the pro-inflammatory response that these drugs produce in HNSCC tumor cells. We found that clinical EGFRIs such as erlotinib, cetuximab, lapatinib and panitumumab induced the secretion of pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-8, GM-CSF, TNFα and IFNγ. Focusing on IL-6, we found that erlotinib induced a time-dependent increase in IL-6 mRNA and protein expression and exogenous IL-6 was able to protect HNSCC cells from erlotinib-induced cytotoxicity. Conversely, an IL-6 receptor antagonist tocilizumab, sensitized HNSCC cells to erlotinib in vitro and in vivo. Inhibitors of NFκB, p38 and JNK suppressed erlotinib-induced IL-6 expression, suggesting an important role of NFκB and MAPK pathways in IL-6 expression. Furthermore, knockdown of NADPH oxidase 4 (NOX4) suppressed erlotinib-induced pro-inflammatory cytokines expression. Taken together, these results suggest that clinical EGFRIs induce the expression of pro-inflammatory cytokines via NOX4. Therefore, the anti-tumor activity of EGFRIs may be partially reduced by activation of NOX4-mediated pro-inflammatory pathways in HNSCC. Total RNA was isolated from Head and Neck Squamous Cell Carcinoma cell lines FADU, SQ20B and Cal 27 subjected to 48 hours of 0.01% DMSO or 5uM EGFR inhibitor, erlotinib treatment.

2014-04-08 | E-GEOD-45891 | biostudies-arrayexpress

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