Targeting IGF2BP2 Promotes Differentiation of Radioiodine Refractory Papillary Thyroid Cancer via Destabilizing RUNX2 mRNA

Simple Summary Differentiation therapy is one of the most promising treatment approaches for radioiodine refractory papillary thyroid cancer (RR-PTC). In this study, we found that insulin-like growth factor 2 mRNA-binding protein 2 promoted dedifferentiation of PTC via integrating to 3 '-untranslated regions of runt-related transcription factor 2, which bound to the promoter region of sodium/iodide symporter, downregulating its expression. N6-methyladenosine (m6A) regulators play an important role in multiple biological and pathological processes of radioiodine refractory papillary thyroid cancer (RR-PTC). However, the function of m6A regulators in differentiation of RR-PTC remains unclear. In this study, online data, clinical samples, and RR-PTC cell lines (K1 and TPC1) were used to identify the m6A regulators that contributed to the differentiation of RR-PTC. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was found to be associated with thyroid-specific genes in online data analyses, and metastatic PTCs with high expression of IGF2BP2 were prone to be I-131-nonavid in clinical analyses. Furthermore, targeting IGF2BP2 increased I-125 uptake in RR-PTC cell lines and enhanced the sodium/iodide symporter (NIS) expression. Mechanistically, IGF2BP2 bound to the m6A modification site of runt-related transcription factor 2 (RUNX2) 3 '-UTR and enhanced the RUNX2 mRNA stability. Moreover, RUNX2 could bind to the promoter region of NIS to block the differentiation of RR-PTC. Together, these results demonstrated that IGF2BP2 represents a diagnostic marker for RR-PTC, suggesting a novel differentiation therapeutic strategy of targeting IGF2BP2.