B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1

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.

Sodium iodide symporter, estrogen receptor, and progesterone receptor expression in carcinoma breast - An immunohistochemical analysis.

Background: Sodium iodide symporter (NIS), a transporter of iodine is essential for thyroid hormone biosynthesis. It also plays a role in the radioiodine treatment of thyroid cancers. NIS mediated radioiodine transport to breast cancers is under active investigation due to its potential therapeutic utility. Cellular localization and quantification using immunohistochemistry may provide clues for its utility in management of carcinoma breast. Materials and Methods: Human NIS (hNIS) expression was therefore assessed by utilizing a rabbit polyclonal antibody raised against a cloned hNIS in different grades of infiltrating duct carcinoma of breast and its metastatic deposits namely in lymph nodes, bone marrow, and endometrium. Further, hNIS expression was compared with prognostic markers namely estrogen receptor (ER) and progesterone receptor (PR). Results: hNIS was positive in 90.6% cases (29/32) and Scarff-Bloom-Richardson grading was done in 25 cases and 23 cases were NIS positive. Among nongraded cases, 2/2 cases of carcinoma in-situ were positive and 4/5 were positive in cases having post therapy residual tumor status. The strong positivity for hNIS was seen irrespective of ER or PR status and of grade of breast carcinoma and correlated well with western blot analysis. In all the three metastatic sites, NIS was positive in the tumor. Conclusion: These findings indicate the utility of immnohistochemistry for NIS as a new potential prognostic marker and may provide guidance for possible radio iodine therapy in breast cancer patients.