Organoid modeling identifies EDN1 as a potential oncogenic driver in papillary thyroid carcinoma via modulation of the Hippo-YAP signaling pathway.

BACKGROUND: Thyroid carcinoma (TC), particularly papillary thyroid carcinoma (PTC), is the most prevalent endocrine malignancy globally. Endothelin-1 (EDN1) has been implicated in tumor progression in various cancers, but its biological role in PTC remains unclear. This study aimed to investigate the expression and function of EDN1 in PTC. METHODS: EDN1 expression in PTC cells and tissues was assessed using RT-qPCR and immunofluorescence. Lentiviral knockdown of EDN1 was performed in PTC cells and organoids. Cell proliferation and migration were evaluated via CCK-8, colony formation, and Transwell assays. The effects of EDN1 inhibition were further examined in PTC organoid and murine xenograft models. Western blotting (WB) and immunofluorescence were used to analyze the expression of proliferation-related (PCNA), migration-related (MMP2), and Hippo-YAP signaling proteins. RESULTS: EDN1 was highly expressed in PTC cells and tissues. Its knockdown significantly suppressed PTC cell proliferation, migration, and tumor growth in xenografts. Additionally, EDN1 deficiency reduced organoid formation efficiency and size. Mechanistically, EDN1 exerted its oncogenic effects partly through the Hippo-YAP pathway. CONCLUSION: Our research findings suggest that EDN1, at least partially through the Hippo-YAP signaling pathway, may exist as a potential oncogenic driver in PTC, suggesting its potential as a diagnostic and therapeutic biomarker for PTC.