MicroRNA signatures associated with radioiodine refractoriness and tumor dedifferentiation in metastatic papillary thyroid carcinoma

Radioiodine (RAI) refractoriness and tumor dedifferentiation are major contributors to poor outcomes in metastatic papillary thyroid carcinoma (PTC). microRNAs (miRNAs) are promising biomarkers to identify these aggressive phenotypes. This study aimed to characterize miRNAs expression profiles associated with RAI refractoriness and dedifferentiation. From a cohort of 108 metastatic PTC patients, 24 cases with available formalin-fixed paraffin-embedded tissue were selected for molecular analysis, including 17 patients who died from disease progression and 7 long-term survivors with stable disease. Total RNA was extracted and analyzed by qPCR. miRNAs with differential expression (P < 0.10) in univariate analysis were included in multivariate linear regression models. Diagnostic performance was assessed using ROC curve analysis and hierarchical clustering. The cohort had a mean age of 55.2 years and was predominantly male (66.7%). RAI-refractory disease was present in 63.2% of evaluable cases, and dedifferentiation in 33.3%. In multivariate analysis, lower expression of miR-200c-3p was independently associated with RAI refractoriness (P = 0.005). For tumor dedifferentiation, higher expression of let-7i-5p (P < 0.001) and miR-19b-3p (P < 0.001), and lower expression of miR-31-5p (P = 0.004) and let-7e-5p (P = 0.036), were independently associated. ROC curve analysis demonstrated high diagnostic accuracy for miR-200c-3p (AUC = 0.929) and let-7i-5p (AUC = 0.958) for, respectively, RAI refractoriness and tumor dedifferentiation. Heatmap analysis revealed clear segregation of phenotypic groups based on miRNA expression. Distinct miRNAs signatures are associated with RAI refractoriness and tumor dedifferentiation in metastatic PTC. These findings support their potential as prognostic biomarkers and may guide future therapeutic stratification.