B-RafV600E mutant is found in 40-70% of papillary thyroid carcinoma (PTC) and has an important role in the pathogenesis of PTC. The sodium iodide symporter (NIS) is an integral plasma membrane glycoprotein that mediates active iodide transport into the thyroid follicular cells, and B-RafV600E has been known to be associated with the loss of NIS expression. In this study, we found that B-RafV600E inhibited NIS expression by the upregulation of its promoter methylation, and that specific regions of CpG islands of NIS promoter in B-RafV600E harboring PTC were highly methylated compared with surrounding normal tissue. Although DNA methyltransferase 3a and 3b (DNMT3a,3b) were not increased by B-RafV600E, DNMT1 expression was markedly upregulated in PTC and B-RafV600E expressing thyrocytes. Furthermore, DNMT1 expression was upregulated by B-RafV600E induced NF-kappaB activation. These results led us to conclude that NIS promoter methylation, which was induced by B-RafV600E, is one of the possible mechanisms involved in NIS downregulation in PTC.
Base Sequence ; Carcinoma/*genetics/metabolism/pathology ; Cells, Cultured ; DNA (Cytosine-5-)-Methyltransferase/analysis/*genetics/metabolism ; DNA Methylation ; Down-Regulation ; *Gene Expression Regulation, Neoplastic ; Humans ; Molecular Sequence Data ; *Point Mutation ; Promoter Regions, Genetic ; Proto-Oncogene Proteins B-raf/*genetics/metabolism ; Symporters/analysis/*genetics/metabolism ; Thyroid Gland/cytology/metabolism/pathology ; Thyroid Neoplasms/*genetics/metabolism/pathology ; Up-Regulation