Abstract
Papillary thyroid cancer (PTC) represents a prevalent endocrine neoplasm. Dysregulated tumor-associated calcium signal transducer 2 (TACSTD2) expression is functionally involved in the progression of multiple cancers. Nonetheless, the biological molecular mechanisms underlying TACSTD2 in PTC remain unclear. To verify the biological function of TACSTD2 in PTC, we conducted loss- and gain-of-function experiments, namely, cell proliferation (Cell Counting Kit-8), EdU incorporation, colony formation, and transwell migration/invasion assays, along with establishing a nude mouse xenograft tumor model. Our findings revealed that TACSTD2 knockout impeded PTC cell proliferation, migration, and invasion in vitro and reduced tumorigenicity in vivo. In contrast, TACSTD2 overexpression reversed these effects in vitro. Through integrated bioinformatics analysis and experimental validation, TACSTD2 was recognized as a downstream target of methyltransferase-like 3 (METTL3)-modulated N6-methyladenosine (m6A) modification. In an m6A-dependent manner, METTL3 reduced TACSTD2 mRNA stability. m6A-mediated degradation of TACSTD2 mRNA was reliant on the m6A reader protein YTHDC2. As evidenced by rescue experiments, TACSTD2 overexpression resulted in a partial restoration of the METTL3-induced tumor-suppressive phenotype. Finally, the METTL3/TACSTD2/YTHDC2 axis was confirmed to be an inhibitor in PTC and activates the TNF signaling to promote cell apoptosis and inhibit the epithelial-mesenchymal transition. Collectively, METTL3-modulated m6A modification of TACSTD2 exerts an indispensable tumor-suppressive function in PTC progression. The METTL3/TACSTD2/YTHDC2 axis may serve as a molecular target for PTC therapy.