N(6)-methyladenosine modification of ADGRA3 by ZC3H13 suppresses papillary thyroid cancer cell malignancy by inactivating the PI3K/Akt/mTOR signaling pathway.

BACKGROUND: N(6)-methyladenosine (m(6)A) modification is a posttranscriptional regulatory mechanism involved in tumorigenesis. Adhesion G protein-coupled receptor A3 (ADGRA3) has been implicated in various biological processes; however, its role in papillary thyroid cancer (PTC) remains unclear. This study investigated the novel regulatory mechanism of ADGRA3 mediated by m(6)A modification and its effect on PTC malignancy, providing new insights into the molecular pathogenesis of PTC. METHODS: The levels of ADGRA3 and ZC3H13 in PTC were analyzed by quantitative reverse-transcription polymerase chain reaction and Western blotting. Cell functional assays, including cell counting kit-8, wound-healing assay, and Transwell assay, were performed to assess PTC malignancy. The levels of the migration and invasion markers were detected through Western blotting. The PI3K/Akt/mTOR pathway was examined through Western blotting for pathway-associated markers. MeRIP and RNA stability assays were utilized to evaluate the regulatory effect of ZC3H13 on ADGRA3. RESULTS: ADGRA3 was downregulated in PTC samples. ADGRA3 overexpression attenuated PTC cells to proliferate, migrate, and invade through the inhibition of the PI3K/Akt/mTOR pathway. ZC3H13 enhanced ADGRA3 mRNA stability by mediating m(6)A modification, and ZC3H13 knockdown reversed the tumor-suppressive effects of ADGRA3 overexpression on the malignant properties of PTC cells. CONCLUSION: This study uncovers a novel regulatory mechanism in which ZC3H13-mediated m(6)A modification of ADGRA3 suppresses PTC cell malignancy by inhibiting the PI3K/Akt/mTOR pathway. These findings highlight the potential of the ZC3H13/ADGRA3 axis as a therapeutic target for PTC, offering a unique and innovative approach to PTC therapy.