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

CNTNAP2 has two isoforms with clear evidence of expression: CNTNAP2-201 and CNTNAP2-203. Extensive research has centered on the full-length CNTNAP2-201, as a neuronal adhesion molecule, due to its association with numerous neurodevelopmental disorders, the role of CNTNAP2-203 in disease pathology has remained largely unexplored. Oral squamous cell carcinoma (OSCC) is a major malignancy in the head and neck region with high mortality and morbidity, partially due to a limited understanding of molecular mechanisms underlying its onset and progression. This study reveals that CNTNAP2-203 mRNA and protein levels are significantly elevated in OSCC tissues compared to their adjacent normal tissues, and high CNTNAP2-203 expression is closely associated with worsened clinical outcomes in OSCC patients. Functionally, CNTNAP2-203 plays a role in driving OSCC cell proliferation in vitro and tumor growth in vivo by modulating E2F1 activity. Mechanistically, CNTNAP2-203 interacts with the epidermal growth factor receptor (EGFR) and amplifies EGFR signal activities, promoting OSCC tumorigenesis through the EGFR-E2F1 axis. Notably, OSCC cells with elevated CNTNAP2-203 demonstrate increased sensitivity to Gefitinib, either alone or in combination with Cisplatin, suggesting patients with high CNTNAP2-203 levels may achieve better outcomes when treated with such regimens. Therefore, this study not only elucidates the pathogenic role of CNTNAP2-203 in OSCC but also highlights the potential of using CNTNAP2-203 as a biomarker for guiding therapeutic strategies in OSCC management. Overall design: To investigate the mechanisms by which CNTNAP2-203 promotes OSCC cell proliferation, we performed RNA-seq analysis on CAL27 cells with CNTNAP2-203 OE.