Dual faces of AREG in OSCC: Reduced circulating levels and enhanced tumor expression suggest compartmentalized regulation

Oral squamous cell carcinoma (OSCC) remains a major global health concern due to its aggressive behavior and poor clinical outcomes, particularly in advanced, technically unresectable cases. The present study adopted a comprehensive multi‑omics approach to identify potential biomarkers and therapeutic targets involved in the progression of OSCC. Differential gene expression analysis revealed 794 upregulated and 1,331 downregulated genes, with 16 genes significantly associated with both overall and disease‑free survival. Among these, amphiregulin (AREG) and C‑X3‑C motif chemokine receptor 1 (CX3CR1) were identified through receiver operating characteristic analysis as the only two genes with a meaningful association with T4 tumor stage (AREG, upregulated; CX3CR1, downregulated), warranting further investigation. Epigenetic profiling revealed that copy number deletions and methylation changes in CX3CR1 were linked to a decreased expression, supporting its tumor‑suppressive role. By contrast, AREG exhibited upregulation despite Copy Number variation loss, suggesting additional regulatory influences, such as epigenetic or post‑transcriptional mechanisms. Immune cell infiltration analysis demonstrated distinct associations of AREG with CD8⁺ T‑cells and CX3CR1 with neutrophils and CD4⁺ T‑cells, underscoring their role in tumor‑immune interactions. Additionally, elevated DNA integrity ratios and the increased expression of AluY subfamilies were observed in patients with technically unresectable OSCC, suggesting a link between transposable element activity and tumor aggressiveness. Molecular docking and dynamics simulations further identified vinorelbine with high binding affinity for AREG, indicating its potential as therapeutic agents against OSCC. Taken together, these findings provide novel insight into the molecular landscape of OSCC and highlight AREG, CX3CR1 and Alu elements as promising biomarkers for diagnosis and prognosis, as well as targets for future therapeutic interventions.