PTTG and PBF repress the human sodium iodide symporter
PTTG and PBF repress the human sodium iodide symporter
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DOI：
10.1038/sj.onc.1210221
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发表时间：
2007-06-01
期刊：
影响因子：
8
通讯作者：
McCabe, C. J.
中科院分区：
文献类型：
--
作者：
Boelaert, K.;Smith, V. E.;McCabe, C. J.
甲状腺积聚碘的能力为分化型甲状腺癌及其转移灶的放射性碘消融提供了基础。大多数甲状腺肿瘤表现出碘摄取减少，尽管对此机制仍知之甚少。甲状腺肿瘤转化基因（PTTG）是一种与甲状腺肿瘤发病有关的原癌基因。我们现在发现PTTG及其结合因子PBF抑制钠碘同向转运体（NIS）信使RNA（mRNA）的表达，并抑制碘摄取。这一过程至少部分是通过。成纤维细胞生长因子-2。在大鼠FRTL-5细胞中NIS启动子的详细研究中，PTTG和PBF证明通过人上游增强子元件（hNUE）特异性抑制启动子活性。在这个类似于1 kb的元件中，复杂的PAX 8-上游刺激因子1（USF 1）响应元件被证明对基础启动子活性和NIS的PTTG和PBF抑制都是至关重要的。特别是，PTTG的抑制取决于USF 1位点，而不是PAX 8位点。最后，在人原代甲状腺细胞中，PTTG和PBF同样通过hNUE抑制NIS启动子。总之，我们的数据表明，PTTG和PBF在分化型甲状腺癌中的过度表达对NIS基因的活性有深远的影响，因此对疗效有显著影响。放射性碘治疗的虚构性。
The ability of the thyroid to accumulate iodide provides the basis for radioiodine ablation of differentiated thyroid cancers and their metastases. Most thyroid tumours exhibit reduced iodide uptake, although the mechanisms accounting for this remain poorly understood. Pituitary tumour transforming gene (PTTG) is a proto-oncogene implicated in the pathogenesis of thyroid tumours. We now show that PTTG and its binding factor PBF repress expression of sodium iodide symporter (NIS) messenger RNA (mRNA), and inhibit iodide uptake. This process is mediated at least in part through. fibroblast growth factor-2. In detailed studies of the NIS promoter in rat FRTL-5 cells, PTTG and PBF demonstrated specific inhibition of promoter activity via the human upstream enhancer element (hNUE). Within this similar to 1 kb element, a complex PAX8-upstream stimulating factor 1 (USF1) response element proved critical both to basal promoter activity and to PTTG and PBF repression of NIS. In particular, repression by PTTG was contingent upon the USF1, but not the PAX8, site. Finally, in human primary thyroid cells, PTTG and PBF similarly repressed the NIS promoter via hNUE. Taken together, our data suggest that the reported overexpression of PTTG and PBF in differentiated thyroid cancer has profound implications for activity of the NIS gene, and hence significantly impacts upon the ef. ficacy of radioiodine treatment.