TPD54 Downregulates ERK Signaling in Oral Squamous Cell Carcinoma Cells

Background/Objectives: Epidermal growth factor receptor is frequently overexpressed in oral squamous cell carcinoma (OSCC) and is associated with poor prognosis. We previously demonstrated that members of the tumor protein D (TPD) 52 family regulate the malignant behavior of OSCC cells and that epidermal growth factor (EGF) induces TPD52 expression. In this study, we investigated the relationship between the TPD52 family and EGF signaling, focusing on TPD54. Methods: SAS OSCC cells were treated with EGF and gefitinib, and the expression of TPD52 family members (TPD52, TPD53, and TPD54) was analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Nascent RNA and RNA degradation assays were conducted to investigate the mechanisms regulating TPD52 family expression. TPD54-overexpressing and TPD54-knockdown cells were used to evaluate EGF signaling, cell cycle progression, proliferation, apoptosis, autophagy, migration, and invasion. Results: EGF stimulation increased the mRNA expression of all TPD52 family members. Nascent RNA analysis revealed increased transcription, whereas RNA degradation assays indicated reduced mRNA stability. TPD54 overexpression attenuated EGF-induced ERK phosphorylation and suppressed EGF-induced cell cycle progression. However, under the present experimental conditions, TPD54 had little effect on cell proliferation, apoptosis, autophagy, migration, or invasion. Conclusions: TPD54 is an EGF-responsive protein that suppresses EGF-induced ERK activation and attenuates cell cycle progression in OSCC cells. Although TPD54 exerted minimal effects on cell proliferation, apoptosis, autophagy, invasion, or migration under the tested conditions, these findings suggest that TPD54 functions as a negative regulator of EGF signaling and provide insight into its molecular role in OSCC.