Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin
Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin
复制标题
DOI：
10.1210/en.2003-1258
复制
发表时间：
2004-06-01
期刊：
影响因子：
4.8
通讯作者：
Kobayashi, T
中科院分区：
文献类型：
--
作者：
Furuya, F;Shimura, H;Kobayashi, T
甲状腺对碘的摄取是由钠/碘同调体介导的。碘摄取后，甲状腺过氧化物酶催化甲状腺球蛋白中酪氨酸残基的碘化，将碘保留在甲状腺滤泡内。在大多数低分化和间变性肿瘤中，癌症中去分化诱导的这些功能丧失，使它们对放射性碘化物无反应。我们重点研究了组蛋白去乙酰化酶（HDAC）抑制剂（HDACI）诱导甲状腺癌细胞分化的方法。我们使用定量RT-PCR和免疫染色技术评估HDACI诱导甲状腺特异性基因mRNA在低分化乳头状和间变性甲状腺癌细胞中的重新表达。检测了HDACI诱导甲状腺特异性基因mrna和蛋白的表达，以及通过碘化一般细胞蛋白来积累放射性碘。影像学实验和体内放射性碘浓度显示，hdaci治疗的肿瘤可特异性积累I-125。为了确定这些基因表达的机制，我们检测了环己亚胺对蛋白质合成的抑制作用，使hdaci处理的细胞中甲状腺过氧化物酶和甲状腺球蛋白mRNA的表达上调，而钠/碘化同调子mRNA的表达下调。总之，我们的研究结果表明，hdaci诱导甲状腺特异性基因的表达，其中一些是由一些蛋白质合成介导的，可能有助于开发新的抗甲状腺癌策略。
Iodide uptake by the thyroid is mediated by the sodium/iodide symporter. Upon iodide uptake, thyroperoxidase catalyzes iodination of tyrosine residues in thyroglobulin, retaining iodide within thyroid follicles. Dedifferentiation-induced loss of these functions in cancers, rendering them unresponsive to radioiodide, occurs with most poorly differentiated and anaplastic tumors. We focused on the histone deacetylase (HDAC) inhibitors (HDACI) as a way to induce differentiation of thyroid cancer cells. We assessed re-expression of thyroid-specific genes mRNA induced by HDACI using quantitative RT-PCR and immunostaining in poorly differentiated papillary and anaplastic thyroid cancer cells. HDACI induced expression of thyroid-specific gene mRNAs and proteins, and accumulation of radioiodide through iodination of generic cellular proteins were detected. HDACI-treated tumors could specifically accumulate I-125 as revealed by imaging experiments and radioiodide concentration in vivo. In an attempt to determine the mechanism by which these gene expressions occurred, we detected the inhibition of protein synthesis by cycloheximide, which up-regulated the expression of thyroperoxidase and thyroglobulin mRNA in HDACI-treated cells and down-regulated that of sodium/iodide symporter mRNA. Together, our results suggest that HDACI-induced expression of thyroid-specific genes, some of which is mediated by some protein synthesis, may contribute to development of novel strategy against thyroid cancer.