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

Authors: Kleiman, D. A.; Buitrago, D.; Crowley, M. J.; Beninato, T.; Veach, A. J.; Zanzonico, P. B.; Jin, M.; Fahey, T. J. 3rd; Zarnegar, R.
Article Title: Thyroid stimulating hormone increases iodine uptake by thyroid cancer cells during BRAF silencing
Abstract: 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.
Keywords: adult; clinical article; controlled study; protein expression; gene mutation; human cell; gene targeting; gene expression; small interfering rna; cancer cell culture; genetic transfection; iodine 131; radioactive iodine; algorithm; cancer cell; thyroid carcinoma; gene silencing; b raf kinase; thyrotropin; sodium iodide symporter; papillary thyroid cancer; thyrotropin receptor; braf (v600e) mutation; radioactive iodine resistance; sodium-iodine symporter; thyroid-stimulating hormone
Journal Title: Journal of Surgical Research
Volume: 182
Issue: 1
ISSN: 0022-4804
Publisher: Academic Press Inc., Elsevier Science  
Date Published: 2013-01-01
Start Page: 85
End Page: 93
Language: English
DOI: 10.1016/j.jss.2012.08.053
PROVIDER: scopus
PMCID: PMC3652238
PUBMED: 22998776
Notes: --- - "Export Date: 3 June 2013" - "CODEN: JSGRA" - "Source: Scopus"
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MSK Authors
  1. Pat B Zanzonico
    246 Zanzonico
  2. Alexander Julian Veach
    2 Veach