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J Mol Endocrinol. 2014 Jan 30;52(2):121-31. doi: 10.1530/JME-13-0160. Print 2014 Apr.

Different expression of TSH receptor and NIS genes in thyroid cancer: role of epigenetics.

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1
Department of Health Sciences, University of Catanzaro 'Magna Graecia', Campus 'S. Venuta', Viale Europa, Germaneto, 88100 Catanzaro, Italy Departments of Internal Medicine and Medical Specialties Surgical Sciences, University of Roma 'Sapienza', 00161 Roma, Italy Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy.

Abstract

The TSH receptor (TSHR) and sodium/iodide symporter (NIS) are key players in radioiodine-based treatment of differentiated thyroid cancers. While NIS (SLC5AS) expression is diminished/lost in most thyroid tumors, TSHR is usually preserved. To examine the mechanisms that regulate the expression of NIS and TSHR genes in thyroid tumor cells, we analyzed their expression after inhibition of ras-BRAF-MAPK and PI3K-Akt-mTOR pathways and the epigenetic control occurring at the gene promoter level in four human thyroid cancer cell lines. Quantitative real-time PCR was used to measure NIS and TSHR mRNA in thyroid cancer cell lines (TPC-1, BCPAP, WRO, and FTC-133). Western blotting was used to assess the levels of total and phosphorylated ERK and Akt. Chromatin immunoprecipitation was performed for investigating histone post-translational modifications of the TSHR and NIS genes. ERK and Akt inhibitors elicited different responses of the cells in terms of TSHR and NIS mRNA levels. Akt inhibition increased NIS transcript levels and reduced those of TSHR in FTC-133 cells but had no significant effects in BCPAP. ERK inhibition increased the expression of both genes in BCPAP cells but had no effects in FTC-133. Histone post-translational modifications observed in the basal state of the four cell lines as well as in BCPAP treated with ERK inhibitor and FTC-133 treated with Akt inhibitor show cell- and gene-specific differences. In conclusion, our data indicate that in thyroid cancer cells the expression of TSHR and NIS genes is differently controlled by multiple mechanisms, including epigenetic events elicited by major signaling pathways involved in thyroid tumorigenesis.

KEYWORDS:

Akt; MAPK; NIS; TSH receptor; epigenetics; thyroid cancer

PMID:
24353283
DOI:
10.1530/JME-13-0160
[Indexed for MEDLINE]
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