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. ABSTRACT: 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 (131)I-nonavid in clinical analyses. Furthermore, targeting IGF2BP2 increased (125)I 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.