Mediator complex subunit 16 is down-regulated in papillary thyroid cancer, leading to increased transforming growth factor-β signaling and radioiodine resistance
Mediator complex subunit 16 is down-regulated in papillary thyroid cancer, leading to increased transforming growth factor-β signaling and radioiodine resistance
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DOI：
10.1074/jbc.ra119.012404
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发表时间：
2020-07-31
影响因子：
4.8
通讯作者：
Bu, Hong
中科院分区：
文献类型：
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作者：
Gao, Hongwei;Bai, Peirong;Bu, Hong
介体复合物亚基16（MED 16）是介体复合物的一个组成部分，在几乎所有RNA聚合酶II依赖性基因的转录事件中起共激活剂的作用。在本研究中，我们报道了与正常甲状腺组织相比，MED 16在甲状腺乳头状癌（PTC）中的表达显著降低，在体外，MED 16在PTC细胞中的过表达显著抑制细胞迁移，增强钠/碘同向转运体表达和碘摄取，并降低对放射性（131）I（RAI）的抗性。相反，其中MED 16已被进一步敲除（MED 16（KD））的PTC细胞表现出增强的细胞迁移，上皮-间充质转化和RAI抗性，伴随着降低的钠/碘同向转运体水平。此外，通过转化生长因子β（TGF-β）的细胞信号传导在MED 16敲低后被高度激活。在MED 12（KD）PTC细胞中获得了类似的结果，并且免疫共沉淀实验验证了MED 16和MED 12之间以及MED 16和TGF-β R2之间的相互作用。值得注意的是，应用LY 2157299（一种有效的TGF-β信号传导抑制剂）在体外和体内均显著减弱了MED 16（KD）诱导的RAI抗性。总之，我们的研究结果表明，PTC中MED 16的减少通过激活TGF-β途径促进肿瘤进展和RAI抗性。
Mediator complex subunit 16 (MED16) is a component of the mediator complex and functions as a coactivator in transcriptional events at almost all RNA polymerase II-dependent genes. In this study, we report that the expression of MED16 is markedly decreased in papillary thyroid cancer (PTC) tumors compared with normal thyroid tissues.In vitro, MED16 overexpression in PTC cells significantly inhibited cell migration, enhanced sodium/iodide symporter expression and iodine uptake, and decreased resistance to radioactive(131)I (RAI). Conversely, PTC cells in which MED16 had been further knocked down (MED16(KD)) exhibited enhanced cell migration, epithelial-mesenchymal transition, and RAI resistance, accompanied by decreased sodium/iodide symporter levels. Moreover, cell signaling through transforming growth factor beta (TGF-beta) was highly activated after the MED16 knockdown. Similar results were obtained in MED12(KD)PTC cells, and a co-immunoprecipitation experiment verified interactions between MED16 and MED12 and between MED16 and TGF-beta R2. Of note, the application of LY2157299, a potent inhibitor of TGF-beta signaling, significantly attenuated MED16(KD)-induced RAI resistance bothin vitroandin vivo. In conclusion, our findings indicate that MED16 reduction in PTC contributes to tumor progression and RAI resistance via the activation of the TGF-beta pathway.