m6A mRNA methylation initiated by METTL₃ inhibits KDR translation to increase the efficacy of ¹³¹I therapy in papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) is a common malignant tumor. ¹³¹I treatment can effectively kill residual PTC microtissues and inhibit metastases. METTL₃ which mediates N6 methyladenosine (m6A) modification participates in the progression of PTC. However, the biomechanism through which METTL₃ regulates ¹³¹I treatment to suppress PTC remains unclear. The mRNA, protein, and m6A levels were detected by RT-qPCR, western blot, and methylated RNA immunoprecipitation (MeRIP) kit respectively. The cell apoptotic ability was measured with flow cytometry (FCM) and TUNEL double staining assays. Transwell assay was used for migration and invasion evaluation. Our results showed that METTL₃ was downregulated in PTC and was upregulated by treating with ¹³¹I. Knockdown of METTL₃ inhibited the suppression of viability, migration, and invasion, and the promotion of apoptosis induced by ¹³¹I treatment. Additionally, METTL₃ was found to bind with KDR, and KDR reversed the effects of METTL₃ knockdown on the biological behaviors of ¹³¹I-treated PTC cells. Furthermore, m6A modification of KDR induced by METTL₃ was recognized by YTHDC2 in PTC, and KDR is a key factor for the PTC progression. (author)