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

David A. Kleiman, Daniel Buitrago, Michael J. Crowley, Toni Beninato, Alexander J. Veach, Pat B. Zanzonico, Moonsoo Jin, Thomas J. Fahey, Rasa Zarnegar

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Background: The 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 BRAF V600E-mutant human thyroid cancer cells. Materials and methods: WRO 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. Results: NIS 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. Conclusions: The 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.

Original languageEnglish (US)
Pages (from-to)85-93
Number of pages9
JournalJournal of Surgical Research
Issue number1
StatePublished - Jun 1 2013


  • BRAF (V600E) mutation
  • Papillary thyroid cancer
  • Radioactive iodine
  • Radioactive iodine resistance
  • Sodium-iodine symporter
  • Thyroid-stimulating hormone

ASJC Scopus subject areas

  • Surgery


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