REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway
REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway
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REGγ 消融阻碍未分化甲状腺癌的去分化，并通过调节 Smad7-TGF-β 途径增强放射治疗反应
DOI：
10.1038/s41418-019-0367-9
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发表时间：
2020-02-01
影响因子：
12.4
通讯作者：
Li, Xiaotao
中科院分区：
文献类型：
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作者：
Jiao, Chan;Li, Lin;Li, Xiaotao
间变性甲状腺癌（ATC）是甲状腺恶性肿瘤中最具侵袭性的一种，以去分化和放射性碘治疗抵抗为特征。调控ATC去分化的潜在机制在很大程度上是未知的。在这里，我们表明，REG γ，一个非经典的蛋白酶体激活剂在ATC中高度表达，是一个重要的调节分化的ATC细胞。在ATC异种移植模型中，REG γ的消融显著恢复了甲状腺特异性基因的表达，增强了碘摄取，并提高了I-131治疗的疗效。在机制上，REG γ直接结合TGF-β信号传导拮抗剂Smad 7并促进其降解，导致TGF-β信号通路的激活。与增益和功能丧失的研究，我们表明，Smad 7是一个重要的调解人的REG γ功能在ATC细胞去分化，这是支持在人类ATC组织中的表达谱。似乎REG γ通过Smad 7降解激活TGF-β信号通路，影响甲状腺特异性基因的抑制和ATC细胞中肿瘤恶性的促进。因此，REG γ可能作为一种新的治疗靶点，允许放射性碘治疗预后不良的甲状腺未分化癌患者。
Anaplastic thyroid cancer (ATC) is the most aggressive human thyroid malignancy, characterized by dedifferentiation and resistance to radioiodine therapy. The underlying mechanisms regulating ATC dedifferentiation are largely unknown. Here, we show that REG gamma, a noncanonical proteasome activator highly expressed in ATC, is an important regulator of differentiation in ATC cells. Ablation of REG gamma significantly restored expression of thyroid-specific genes, enhanced iodine uptake, and improved the efficacy of I-131 therapy in ATC xenograft models. Mechanistically, REG gamma directly binds to the TGF-beta signaling antagonist Smad7 and promotes its degradation, leading to the activation of the TGF-beta signal pathway. With gain- and loss-of-function studies, we demonstrate that Smad7 is an important mediator for the REG gamma function in ATC cell dedifferentiation, which is supported by expression profiles in human ATC tissues. It seems that REG gamma impinges on repression of thyroid-specific genes and promotion of tumor malignancy in ATC cells by activating the TGF-beta signal pathway via degradation of Smad7. Thus, REG gamma may serve as a novel therapeutic target for allowing radioiodine therapy in anaplastic thyroid cancer patients with poor prognosis.