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Changes in cell junctions induced by inhibition of epidermal growth factor receptor in oral squamous cell carcinoma cells.

ABSTRACT: The benefits of epidermal growth factor receptor (EGFR) targeting in the treatment of head and neck cancer, have been documented. However, a minority of patients with head and neck cancer are unresponsive to EGFR targeting therapies. The present study evaluated the effects and limitations of an EGFR inhibitor on oral squamous cell carcinoma cells, particularly on cell-cell junctions mediated by epithelial (E)-cadherin. HSC-3 oral squamous cell carcinoma cells were treated with the EGFR inhibitor, AG1478 (0, 0.5, 2, 10 and 50 µM), and the effects of EGFR inhibition in HSC-3 cells were evaluated by wound healing assays, E-cadherin immunostaining and measurement of transepithelial electrical resistance in vitro. It was observed that treatment of oral squamous cell carcinoma cells with AG1478 suppressed cell motility, altered cell morphology and increased the number of cell-cell junctions compared with untreated control cells. Knockdown of EGFR induced a similar phenotype to that observed by the inhibition of EGFR. Furthermore, in oral squamous cell carcinoma cells treated with high-dose EGFR inhibitor (50 µM), the small number of cells that survived formed cell-cell junctions that were positive for E-cadherin expression. In cells treated with low concentrations of EGFR inhibitor (2 µM), recovery of epithelial properties was observed. The retention of E-cadherin expression in cells that survived high-dose EGFR inhibitor treatment may be a survival mechanism of cancer cells.

SUBMITTER: Kakei Y

PROVIDER: S-EPMC5525654 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:BackgroundThe tumor-specific EGFR deletion mutant, EGFRvIII, is characterised by ligand-independent constitutive signalling. Tumors expressing EGFRvIII are resistant to current EGFR-targeted therapy. The frequency of EGFRvIII in head and neck squamous cell carcinoma (HNSCC) is disputed and may vary by specific sub-site. The purpose of this study was to measure the occurrence of EGFRvIII mutations in a specific HNSCC subsite, oral squamous cell carcinoma (OSCC), using a novel real-time PCR assay.MethodologyPre-treatment Formalin Fixed Paraffin Embedded (FFPE) cancer specimens from 50 OSCC patients were evaluated for the presence of EGFRvIII using a novel hydrolysis probe-based real-time PCR assay. EGFR protein expression in tumor samples was quantified using fluorescent immunohistochemistry (IHC) and AQUA® technology.Principal findingsWe detected EGFRvIII in a single OSCC patient in our cohort (2%). We confirmed the validity of our detection technique in an independent cohort of glioblastoma patients. We also compared the sensitivity and specificity of our novel real-time EGFRvIII detection assay to conventional RT-PCR and direct sequencing. Our assay can specifically detect EGFRvIII and can discriminate against wild-type EGFR in FFPE tumor samples. AQUAnalysis® revealed that the presence of EGFRvIII transcript is associated with very high EGFR protein expression (98(th) percentile). Contrary to previous reports, only 44% of OSCC over-expressed EGFR in our study.Conclusion and significanceOur results suggest that the EGFRvIII mutation is rare in OSCC and corroborate previous reports of EGFRvIII expression only in tumors with extreme over-expression of EGFR. We conclude that EGFRvIII-specific therapies may not be ideally suited as first-line treatment in OSCC. Furthermore, highly specific and sensitive methods, such as the real-time RT-PCR assay and AQUAnalysis® described here, will provide accurate assessment of EGFR mutation frequency and EGFR expression, and will facilitate the selection of optimal tailored therapies for OSCC patients.

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Changes in cell junctions induced by inhibition of epidermal growth factor receptor in oral squamous cell carcinoma cells.

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