EP4 stimulation promotes cell adhesion and migration via IL-6 signaling in oral squamous cell carcinoma

Oral squamous cell carcinoma cell (OSCC) comprises malignant neoplasms arising within the oral cavity. Early-stage detection is associated with favorable prognosis, whereas progression to advanced stages with lymph node metastasis significantly worsens outcomes. We previously reported that the prostaglandin E₂ (PGE₂) receptor EP4 regulates OSCC migration. RNA sequencing reanalysis suggested that EP4 stimulation is strongly associated with cell migration and adhesion, with interleukin-6 (IL-6) emerging as a central mediator of these processes. In OSCC cells, ONO-AE1–437 (EP4 agonist) increased IL-6 mRNA expression and protein secretion. EP4-overexpressing cells showed increased IL-6 expression without stimulation, further enhanced by ONO-AE1–437 or PGE₂. xCELLigence demonstrated that PGE₂ promoted cell adhesion, which was suppressed by ONO-AE3–208 (EP4 antagonist) and Tocilizumab (IL-6 inhibitor). Scratch and transwell assays revealed enhanced migration under PGE₂ and ONO-AE1–437, blocked by IL-6 inhibition. These results suggest that EP4 promotes cell adhesion and migration through IL-6 in OSCC cells. (147 words)