Cadherin-mediated cell adhesion networks drive tumor growth and therapeutic responses in head and neck cancer.

Cadherin family genes (CDH1, CDH2, and CDH3) regulate cell-cell adhesion and epithelial integrity and have emerging roles in tumorigenesis. However, their molecular and functional relevance in Head and Neck Squamous Cell Carcinoma (HNSC) remains incompletely defined. Cadherin expression was evaluated in HNSC and normal oral epithelial cell lines using RT-qPCR. Multi-omics analyses of transcriptomic, methylation, mutation, and copy number variation (CNV) data were performed using TCGA datasets through GSCA, OncoDB, cBioPortal, and UALCAN. Prognostic significance was assessed using Kaplan-Meier and meta-analysis approaches. miRNA-mRNA interactions were predicted using miRNet and validated experimentally. Immune associations, drug sensitivity, and protein-protein interactions were explored using TISIDB, GSCA, STRING, and DAVID. Functional effects of CDH1 and CDH2 were evaluated by siRNA knockdown in FaDu and SCC9 cells, followed by proliferation, colony formation, wound healing, and xenograft assays. CDH1, CDH2, and CDH3 were significantly upregulated in HNSC cell lines and TCGA tumor samples, with CDH3 showing the highest diagnostic accuracy (AUC = 0.90). Hypomethylation and CNV amplification contributed to cadherin dysregulation, particularly for CDH2 and CDH3. Elevated cadherin expression correlated with poor overall survival. miR-200a-3p and miR-200c-3p were identified as shared regulators. Cadherin expression also showed associations with immune modulators and drug response. Functionally, CDH1 and CDH2 knockdown suppressed proliferation, migration, and tumor growth. Cadherin genes, particularly CDH3, show diagnostic and prognostic relevance in HNSC, while CDH1 and CDH2 contribute to tumor cell growth and migration. Further studies are required to determine their therapeutic potential.