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J Surg Res. 2013 Jun 1;182(1):85-93. doi: 10.1016/j.jss.2012.08.053. Epub 2012 Sep 8.

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

Author information

1
Division of Endocrine and Minimally Invasive Surgery, Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York, USA.

Abstract

BACKGROUND:

The BRAF(V600E) 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 (131)I uptake of BRAF(V600E)-mutant human thyroid cancer cells.

MATERIALS AND METHODS:

WRO cells (a BRAF(V600E)-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 (131)I 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, (131)I 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 (131)I 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.

PMID:
22998776
PMCID:
PMC3652238
DOI:
10.1016/j.jss.2012.08.053
[Indexed for MEDLINE]
Free PMC Article
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