Epidermal growth factor receptor (EGFR) activation is a major cause of cell metastasis in many cancers, such as head and neck squamous cell carcinoma (HNSCC). However, whether the induction of cyclooxygenase-2 (COX-2) correlates with EGF-enhanced HNSCC metastasis remains unclear. Interestingly, we found that EGF induced COX-2 expression mainly in HNSCC. The tumor cell transformation induced by EGF was repressed with COX-2 knockdown, and this repression was reversed by simultaneously treating the cells with EGF and prostaglandin E2 (PGE2). The down-regulation of COX-2 expression or inhibition of COX-2 activity significantly blocked EGF-enhanced cell migration and invasion, but the addition of PGE2 compensated for this blockage in COX-2-knockdown cells. Interestingly, COX-2 depletion inhibited EGF-induced matrix metalloproteinase-1 (MMP-1), MMP3 and fibronectin expression and Rac1/cdc42 activation; this reduction in MMPs and the fibronectin/Rac1/cdc42 axis by the depletion of COX-2 was also rescued when the cells were treated with PGE2. Furthermore, the depletion of fibronectin impeded the COX-2-enhanced binding of HNSCC cells to endothelial cells and tumor cells metastatic seeding of the lungs. These results provide new insight that EGF-induced COX-2 enhances HNSCC metastasis via activation of the fibronectin signaling pathway. The inhibition of COX-2 expression and activation suggests a potential strategy for the treatment of EGFR-mediated HNSCC metastasis.
Date:
2015-08
Relation:
Cancer Research. 2015 Aug;75(Suppl. 15):Abstract number 4149.
