CNTNAP2–203 interaction with EGFR modulates E2F1 activity and promotes tumorigenesis in oral squamous cell carcinoma

CNTNAP2 has two isoforms with confirmed expression: CNTNAP2-201 and CNTNAP2-203. While extensive research has focused on CNTNAP2-201 due to its association with various neurodevelopmental disorders, the role of CNTNAP2-203 in disease pathology remains largely unexplored. Oral squamous cell carcinoma (OSCC) is a major malignancy with high mortality, partially due to limited understanding of its molecular mechanisms. This study demonstrates that CNTNAP2-203 is predominantly expressed and significantly upregulated in OSCC tissues, and elevated CNTNAP2-203 is associated with poorer clinical outcomes. Functionally, CNTNAP2-203 promotes OSCC cell proliferation in vitro and tumor growth in vivo by positively modulating the activity of E2F transcription factor 1 (E2F1), a transcription factor that regulates G1/S cell cycle progression. Mechanistically, CNTNAP2-203 interacts with the epidermal growth factor receptor (EGFR), enhancing EGFR signaling and promoting OSCC tumorigenesis via the EGFR-E2F1 axis. Notably, OSCC cells with elevated CNTNAP2-203 exhibit increased sensitivity to Gefitinib (an EGFR tyrosine kinase inhibitor), either alone or in combination with Cisplatin, suggesting that patients with elevated CNTNAP2-203 may benefit from these treatments. In summary, this study not only elucidates the pathogenic role of CNTNAP2-203 in OSCC but also identifies it as a promising biomarker for guiding therapeutic strategies in OSCC management.