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Title: Hypermethylation of a New Distal Sodium/Iodide Symporter (NIS) Enhancer (NDE) Is Associated With Reduced NIS Expression in Thyroid Tumors
Authors: Galrao, Ana Luiza
Camargo, Rosalinda Y.
Friguglietti, Celso U.
Moraes, Lais [UNIFESP]
Cerutti, Janete Maria [UNIFESP]
Serrano-Nascimento, Caroline
Suzuki, Miriam F.
Medeiros-Neto, Geraldo
Rubio, Ileana Gabriela Sanchez de [UNIFESP]
Universidade de São Paulo (USP)
Head & Neck Surg Santa Catarina Hosp
Universidade Federal de São Paulo (UNIFESP)
Issue Date: 1-Jun-2014
Publisher: Endocrine Soc
Citation: Journal of Clinical Endocrinology & Metabolism. Washington: Endocrine Soc, v. 99, n. 6, p. E944-E952, 2014.
Abstract: Context: in thyroid tumors, reduced radioiodine uptake is associated with worse patient outcome concomitantly with low sodium/iodide symporter (NIS) mRNA expression. Previous studies showed that CpG-island methylation in the NIS proximal promoter does not correlate with mRNA expression.Objectives: the aim of the study was to identify new CpG-islands within the NIS 5' region and investigate the involvement of their methylation in NIS expression.Design: DNA was obtained from 30 pairs of thyroid samples: tumor (T) and surrounding nontumor (NT) samples. All T samples had reduced NIS mRNA expression compared to NT samples.Main Outcome Measures: Methylation degree was quantified by bisulfite sequencing, and NIS expression by real-time PCR and Western blot. Reporter gene assays were performed to determine CpG-island functionality. Tumor cell cultures were treated with 5-Aza demethylating agent to determine NIS expression, methylation status, and I-125 uptake.Results: We identified a new CpG-island2 with 14 CpG sites, located -2152/-1887 relative to ATG site. CpG-island2 was hypermethylated in T compared to NT samples, in both benign and malignant tumor groups. There was a significant inverse correlation between NIS mRNA expression and degree of CpG-island2 methylation in NT and T samples. This sequence increased the expression of a reporter gene; thus, it was considered a new enhancer. Cell culture treatments with 5-Aza reduced CpG-island2 methylation levels concomitantly with restoration of NIS mRNA and protein expression and I-125 uptake.Conclusions: We identified a new distal enhancer, NIS distal enhancer, that regulates gene expression through DNA methylation. This enhancer is hypermethylated in T compared to NT samples and is associated with decreased NIS expression in tumors. This epigenetic deregulation may be an early event in tumorigenesis.
ISSN: 0021-972X
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