CNTNAP2203 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 CNTNAP2201 due to its association with various neurodevelopmental disorders, the role of CNTNAP2203 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 CNTNAP2203 is predominantly expressed and significantly upregulated in OSCC tissues, and elevated CNTNAP2203 is associated with poorer clinical outcomes. Functionally, CNTNAP2203 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, CNTNAP2203 interacts with the epidermal growth factor receptor (EGFR), enhancing EGFR signaling- and promoting OSCC tumorigenesis via the EGFRE2F1 axis. Notably, OSCC cells with elevated CNTNAP2203 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.