Abstract:Background and Aims Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, yet the molecular mechanisms underlying its invasion and metastasis remain unclear. This study aimed to investigate the role of the transcription factor ETV4 in PTC and its regulatory relationship with cadherin-3 (CDHP/CDH3).Methods Expression levels of ETV4 and CDHP were analyzed using TCGA and GTEx databases, and further validated in normal thyroid cells and multiple PTC cell lines by qRT-PCR and Western blot analysis. ETV4-knockdown models were established using siRNA, and changes in CDHP expression and cellular behaviors were assessed by qRT-PCR, Western blot, CCK-8, wound healing, and Transwell assays.Results Bioinformatics analysis revealed significantly higher expression of ETV4 and CDHP in PTC tissues compared to normal thyroid tissues (P<0.001). Correlation analysis demonstrated a strong positive association between ETV4 and CDHP expression (R2>0.5, P<0.01). In vitro assays confirmed that both ETV4 and CDHP were upregulated in all tested PTC cell lines at the mRNA and protein levels (all P<0.05). Knockdown of ETV4 led to marked reduction of CDHP expression (P<0.05), accompanied by decreased cell proliferation, migration, and invasion as demonstrated by CCK-8, wound healing, and Transwell assays (all P<0.05).Conclusion ETV4 may transcriptionally upregulates CDHP to promote proliferation, migration, and invasion of PTC cells. The ETV4/CDHP axis may serve as a novel biomarker and potential therapeutic target in PTC.