Thyroid stimulating hormone increases iodine uptake by thyroid cancer cells during BRAF silencing

BackgroundThe BRAFV600E mutation is present in 62% of radioactive iodine–resistant thyroid tumors and is associated with downregulation of the sodium–iodide symporter (NIS) and thyroid stimulating hormone receptor (TSHr). We sought to evaluate the combined effect of BRAF inhibition and TSH supplementation on 131I uptake of BRAFV600E-mutant human thyroid cancer cells.Materials and methodsWRO cells (a BRAFV600E-mutant follicular-derived papillary thyroid carcinoma cell line) were transfected with small interfering RNA targeting BRAF for 72 h in a physiological TSH environment. NIS and TSHr expression were then evaluated at three levels: gene expression, protein levels, and 131I uptake. These three main outcomes were then reassessed in TSH-depleted media and media supplemented with supratherapeutic concentrations of TSH.ResultsNIS gene expression increased 5.5-fold 36 h after transfection (P = 0.01), and TSHr gene expression increased 2.8-fold at 24 h (P = 0.02). NIS and TSHr protein levels were similarly increased 48 and 24 h after transfection, respectively. Seventy-two hours after BRAF inhibition, 131I uptake was unchanged in TSH-depleted media, increased by 7.5-fold (P < 0.01) in physiological TSH media, and increased by 9.1-fold (P < 0.01) in supratherapeutic TSH media.ConclusionsThe combined strategy of BRAF inhibition and TSH supplementation results in greater 131I uptake than when either technique is used alone. This represents a simple and feasible approach that may improve outcomes in patients with radioactive iodine–resistant thyroid carcinomas for which current treatment algorithms are ineffective.