Zhu Lin, Ma Suzhen, Jiang Binyuan, Gu Yunyan, Ye Yu, Xiong Haofeng, Su Tong, Wang Danling
Hengyang Medical School, University of South China, Hengyang, Hunan, China; Institute for Future Sciences, University of South China, Changsha, Hunan, China; MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, University of South China, Changsha, Hunan, China.
The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China.
Cell Signal. 2025 Nov;135:112059. doi: 10.1016/j.cellsig.2025.112059. Epub 2025 Aug 10.
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.
