Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation

Abstract

Epidermal Growth Factor Receptor (EGFR) is frequently over-expressed in head and neck squamous cell carcinoma (HNSCC) where aberrant signaling downstream of this receptor contributes to tumor growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. We previously reported that EGFRvIII is expressed in up to 40% of HNSCC tumors where it is associated with increased proliferation, tumor growth and chemoresistance to anti-tumor drugs including the EGFR targeting monoclonal antibody cetuximab. Cetuximab was FDA-approved in 2006 for HNSCC but has not been shown to prevent invasion or metastasis. The present study was undertaken to evaluate the mechanisms of EGFRvIII-mediated cell motility and invasion in HNSCC. We found that EGFRvIII induced HNSCC cell migration and invasion in conjunction with increased STAT3 activation, which was not abrogated by cetuximab treatment. Further investigation demonstrated that EGF-induced expression of the STAT3 target gene HIF1-α, was abolished by cetuximab in HNSCC cells expressing wild-type EGFR under hypoxic conditions, but not in EGFRvIII-expressing HNSCC cells. These results suggest that EGFRvIII mediates HNSCC cell migration and invasion via increased STAT3 activation and induction of HIF1-α, which contribute to cetuximab resistance in EGFRvIII-expressing HNSCC tumors.

EGFR and NF-κB: partners in cancer

“…The EGFR-targeting cetuximab used in combination with radiation prolonged overall survival but failed to reduce the incidence of metastasis, and the response rate with cetuximab administered alone is not above 13% [59]. One mechanism underlying resistance to cetuximab results from the expression of the EGFRvIII mutant, which has a truncated ligand-binding domain, and signals to Lyn, a member of the SRC family of kinases and to STAT3 in up to 42% cases of HNSCC [60,61]. Although the EGFR inhibitor gefitinib showed some response in clinical trials of HNSCC by decreasing EGFR, MEK1, and NF-kB p65 phosphorylation, it failed to interfere with these oncogenic pathways in nonresponder patients [62].…”

Mechanisms of Invasion in Head and Neck Cancer

“…The role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in HNSCC invasion is complex. STAT3 is important for ligand-independent invasion induced by the EGFR vIII isoform, 96 but JAK2-STAT5a signaling is important for erythropoietin (EPO)-induced invasion but not EGF-induced invasion.…”

Regulation of cell migration via the EGFR signaling pathway in oral squamous cell carcinoma cells

“…EGFR stimulation induces cell migration through the activation of matrix metalloproteinases (MMPs) (24), signal transducer and activator of transcription 3 (STAT3) (25,26) or the MEK/ERK and PI3K signaling pathways (9), and may be associated with an epithelial-mesenchymal transition (EMT)-like phenotype (27). Furthermore, cross-talk between EGFR and G-protein-coupled receptors contributes to cell migration (28,29).…”