PDZD11 as a Potential Mediator of Radioresistance in HPV-Negative HNSCC: Implications for Adherens Junction and Calcium Signaling

Background Radioresistance (RR) drives treatment failure in head and neck squamous cell carcinoma (HNSCC), especially in HPV-negative subtype lacking targeted therapies. This study investigates the role of the scaffold protein PDZ Domain Containing 11 (PDZD11) in driving this resistant phenotype. Methods Integrative bioinformatics of GEO datasets (GSE210922, GSE182227) identified PDZD11 as a top candidate. Clinical relevance was assessed using TCGA, Kaplan-Meier survival, and immunohistochemistry (IHC) on a patient cohort. A isogenic radioresistant cell line (HN30-RR) was established from HPV-negative HN30 cells. Functional roles were characterized via siRNA-mediated knockdown, clonogenic survival, apoptosis assays, qPCR, and Western blot. Results PDZD11 was overexpressed in HNSCC, with high expression correlating with poor prognosis (HR=1.55, p=0.0012) and HPV-negative status (p<0.0001). The HN30-RR model demonstrated enhanced clonogenic survival and reduced apoptosis. Crucially, radiation triggered a 3.72-fold PDZD11 upregulation specifically in HN30-RR cells, absent in sensitive counterparts. siRNA-mediated PDZD11 knockdown achieved efficient silencing in HN30-RR cells (p<0.0001), providing a basis for future investigation of its role in radiosensitivity. Conclusion PDZD11 is a candidate mediator of radioresistance in HPV-negative HNSCC, with potential implications for radiosensitization. PDZD11 inhibition may disrupt resistance through destabilizing adherens junctions and dysregulating calcium-mediated death, positioning it as a promising radiosensitizing target.