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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 7 2449-2457
Copyright © 1999 by The Endocrine Society

Original Studies

Restoration of Iodide Uptake in Dedifferentiated Thyroid Carcinoma: Relationship to Human Na+/I- Symporter Gene Methylation Status1

Gopalakrishnan M. Venkataraman, Mustafa Yatin, Regina Marcinek and Kenneth B. Ain

Thyroid Cancer Research Laboratory, Medical Service, Veterans Affairs Medical Center, Lexington, Kentucky 40511; and the Division of Endocrinology and Molecular Medicine, Department of Internal Medicine, University of Kentucky Medical Center, Lexington, Kentucky 40536-0084

Address all correspondence and requests for reprints to: Kenneth B. Ain, M.D., Thyroid Nodule and Oncology Clinical Service, Division of Endocrinology and Molecular Medicine, Department of Internal Medicine, Room MN520, University of Kentucky Medical Center, 800 Rose Street, Lexington, Kentucky 40536-0084. E-mail: kbain1{at}pop.uky.edu

Disseminated dedifferentiated thyroid epithelial carcinoma, which cannot sufficiently concentrate therapeutic radioiodide, is a terminal disease without any effective systemic treatment or chemotherapy. This is a likely consequence of loss of human sodium-iodide symporter (hNIS) function. We hypothesized that hNIS transcriptional failure in thyroid carcinoma could be consequent to methylation of DNA in critical regulatory regions and could be reversed with chemical demethylation treatment. Analysis of hNIS messenger ribonucleic acid (mRNA) expression in 23 tumor samples revealed that although loss of this expression corresponded to loss of clinical radioiodide uptake, some thyroid carcinomas with hNIS mRNA expression did not concentrate iodide, suggesting additional posttranscriptional mechanisms for loss of hNIS function. In addition, analysis of DNA methylation in CpG-rich regions of the hNIS promoter extending to the first intron failed to define specific methylation patterns associated with transcriptional failure in human thyroid tumor samples. In seven human thyroid carcinoma cell lines lacking hNIS mRNA, treatment with 5-azacytidine or sodium butyrate was able to restore hNIS mRNA expression in four cell lines and iodide transport in two cell lines. Investigation of methylation patterns in these cell lines revealed that successful restoration of hNIS transcription was associated with demethylation of hNIS DNA in the untranslated region within the first exon. This was also associated with restoration of expression of thyroid transcription factor-1. These results suggest a role for DNA methylation in loss of hNIS expression in thyroid carcinomas as well as a potential application for chemical demethylation therapy in restoring responsiveness to therapeutic radioiodide.




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