Choi Yong Won, Kim Hyun-Ju, Kim Young Hwa, Park So Hyun, Chwae Yong Jun, Lee Jeonghun, Soh Euy Young, Kim Jang-Hee, Park Tae Jun
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
Department of Microbiology, Ajou University School of Medicine, Suwon, Korea.
Exp Mol Med. 2014 Nov 7;46(11):e120. doi: 10.1038/emm.2014.68.
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-κB 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.
在40%-70%的甲状腺乳头状癌（PTC）中发现了B-RafV600E突变体，其在PTC的发病机制中起重要作用。碘化钠同向转运体（NIS）是一种完整的质膜糖蛋白，介导碘离子主动转运进入甲状腺滤泡细胞，已知B-RafV600E与NIS表达缺失有关。在本研究中，我们发现B-RafV600E通过上调其启动子甲基化来抑制NIS表达，并且与周围正常组织相比，携带B-RafV600E的PTC中NIS启动子的CpG岛特定区域高度甲基化。尽管B-RafV600E不会增加DNA甲基转移酶3a和3b（DNMT3a、3b），但在PTC和表达B-RafV600E的甲状腺细胞中，DNMT1表达明显上调。此外，B-RafV600E诱导的NF-κB激活会上调DNMT1表达。这些结果使我们得出结论，B-RafV600E诱导的NIS启动子甲基化是PTC中NIS下调的可能机制之一。
