EGF/EGFR Promotes Salivary Adenoid Cystic Carcinoma Cell Malignant Neural Invasion via Activation of PI3K/AKT and MEK/ERK Signaling

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.

11‐Ethoxyviburtinal improves chronic restraint stress‐induced anxiety‐like behaviors in gender‐specific mice via PI3K/Akt and E2/ERβ signaling pathways

“…The docking scores were −6.8 kcal/ mol, −4.7 kcal/ mol, −5.8 kcal/mol, and −6.6 kcal/mol, respectively, indicating that 11‐ethoxyviburtinal provided anxiolytic‐like effects by acting on these receptors (Table S2). Since two of the four core targets (AKT1 and PIK3CA) are from the PI3K/Akt signaling pathway, and EGFR can also activate this pathway (Chen et al, 2022; Ren et al, 2022), this pathway was regarded as one of the objects of verification.…”

HHLA2 deficiency inhibits pancreatic cancer progression and THP-1 macrophage M2 polarization via EGFR/MAPK/ERK and mTOR/AKT pathway

“…Aberrant activation of the EGFR/MAPK/mTOR/AKT/ERK1/2 signaling pathway occurs in a variety of human cancer cells [ 35 ]. EGFR is a tyrosine kinase-type receptor that is commonly activated or overexpressed in a variety of cancers, and the MAPK/ERK signaling pathway mediates the biological effects of EGFR activation [ 36 , 37 ]. The AKT-mTOR signaling cascade is involved in several physiological and pathological processes, and mTOR is one of the downstream kinases of the AKT signaling pathway.…”

Near-Infrared Photoimmunotherapy Using a Protein Mimetic for EGFR-Positive Salivary Gland Cancer

“…Approximately 40–70% of salivary gland cancers overexpress EGFR, and EGFR overexpression in recurrent or metastatic SGC was detected in 77.8% of cases [ 11 , 12 , 31 , 32 ]. Moreover, EGFR expression is associated with aggressive behaviors such as nerve invasion and impaired saliva production [ 33 , 34 , 35 ]. Therefore, NIR-PIT using the EGFR Affibody–IR700Dye conjugate is highly effective.…”