Restoration of iodide uptake in dedifferentiated thyroid carcinoma: Relationship to human Na+/I- symporter gene methylation status

Disseminated dedifferentiated thyroid epithelial carcinoma, which cannot su fficiently concentrate therapeutic radioiodide, it; a terminal disease with out any effective systemic treatment or chemotherapy. This is a likely cons equence of loss of human sodium-iodide symporter (hNIS) function. We hypoth esized that hNIS transcriptional failure in thyroid carcinoma could be cons equent to methylation of DNA in critical regulatory regions and could be re versed with chemical demethylation treatment. Analysis of hNIS messenger ri bonucleic acid (mRNA) expression in 23 tumor samples revealed that although loss of this expression corresponded to loss of clinical radioiodide uptak e, some thyroid carcinomas with hNIS mRNA expression did not concentrate io dide, 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 m ethylation patterns associated with transcriptional failure in human thyroi d tumor samples. In seven human thyroid carcinoma cell lines lacking hNIS m RNA, treatment with 5-azacytidine or sodium butyrate was able to restore hN IS mRNA expression in four cell lines and iodide transport in two cell line s. Investigation of methylation patterns in these cell lines revealed that successful restoration of hNIS transcription was associated with demethylat ion of hNIS DNA in the untranslated region within the first exon. This was also associated with restoration of expression of thyroid transcription fac tor-1. These results suggest a role for DNA methylation in loss of hNIS exp ression in thyroid carcinomas as well as a potential application for chemic al demethylation therapy in restoring responsiveness to therapeutic radioio dide.