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BACKGROUND Salivary adenoid cystic carcinoma (SACC) is one of the most common malignant cancers of the salivary gland, and 32.4-72.0% of SACC cases exhibit neural invasion (NI), however, the molecular… Click to show full abstract
BACKGROUND Salivary adenoid cystic carcinoma (SACC) is one of the most common malignant cancers of the salivary gland, and 32.4-72.0% of SACC cases exhibit neural invasion (NI), however, the molecular mechanism underlying the high invasion potential of SACC remains unclear. METHODS The present study investigated the role of epidermal growth factor receptor (EGFR) in the AKT inhibition- or mitogen-activated protein kinase kinase (MEK)-induced NI and epithelial-mesenchymal transition (EMT) in SACC cells using EGFR, PI3K and MEK inhibitors. SACC 83 cell viability was assessed using an MTT assay, and a wound healing assay was performed to evaluate cell migration. Immunohistochemical staining with streptavidin peroxidase was used to detect the positive expression rate of EMT, AKT, phosphorylated (p)-AKT, ERK and p-ERK proteins. The impact of EGFR, PI3K and MEK inhibitors on tumor growth and NI was examined in a xenograft model in nude mice. RESULTS EGF and EGFR are effective in increasing cell viability, migration and invasion. SACC metastasis is affected by the PI3K/AKT and MEK/ERK pathways, both of which are initiated by EGF/EGFR. The EMT and NI are regulated by the EGF/EGFR, PI3K/AKT and MEK/ERK pathways. The present findings demonstrate the importance of suppressed EGFR/AKT/MEK signaling in NI in SACC by neural-tumor co-culture in vitro. Furthermore, our preclinical experiment provides solid evidence that injection of EGFR, PI3K and MEK inhibitors obviously suppressed the tumor growth and NI of SACC cells in nude mice. CONCLUSION It was identified that inhibitors of EGFR, PI3K/AKT or MEK/ERK suppressed the proliferation, migration and NI of SACC-83 cells via downregulation of the PI3K/AKT or MEK/ERK pathways. It was also demonstrated that inhibition of EGFR abolishes EMT in SACC by inhibiting the signaling of PI3K/AKT and MEK/ERK. The present results suggest the potential effectiveness of targeting multiple oncogenes associated with downstream pathways of EGF/EGFR, as well as potential therapeutic targets to limit NI in SACC by PI3K/AKT or MEK/ERK inhibition.