Activation of the RhoB signaling pathway by thyroid hormone receptor β in thyroid cancer cells.
Activation of the RhoB signaling pathway by thyroid hormone receptor β in thyroid cancer cells.
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DOI：
10.1371/journal.pone.0116252
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kitamura K
中科院分区：
文献类型：
--
作者：
Ichijo S;Furuya F;Shimura H;Hayashi Y;Takahashi K;Ohta K;Kobayashi T;Kitamura K
甲状腺激素受体（TR）介导甲状腺激素（T3）对细胞生长、发育和分化的关键作用。在人类肝癌、乳腺癌、肺癌和甲状腺癌中已发现TR的表达降低或失活体细胞突变。TR相关的致癌机制尚不清楚。为研究TRβ在甲状腺癌细胞增殖中的作用，构建了表达人TRβ1 cDNA的重组腺病毒载体AdTRβ。用腺病毒介导的TRβ感染TRβ蛋白表达水平明显低于正常甲状腺组织的甲状腺癌细胞株，分析TRβ对细胞增殖和迁移的影响。配体结合的TRβ诱导HDAC 1和HDAC 3从与RhoB启动子相关的组蛋白乙酰化中解离，并增强RhoB mRNA和蛋白的表达。在AdTRβ感染的细胞中，T3和法尼基转移酶抑制剂（FTI）处理诱导RhoB在细胞膜上的分布，并增加活性GTP结合的RhoB的丰度。这种RhoB蛋白导致p21相关的细胞周期停滞在G 0/G1期，抑制细胞增殖和侵袭。相反，在AdTRβ感染的细胞中，通过小干扰RNA敲低降低细胞RhoB导致p21下调并抑制细胞周期停滞。与注射病毒的对照肿瘤相比，注射AdTRβ并进行FTIs治疗可显著抑制BHP 18 - 21 v肿瘤异种移植物的体内生长。这种由配体结合的TRβ触发的新信号通路为甲状腺癌的增殖和侵袭提供了可能的机制，并可能为甲状腺癌提供新的治疗靶点。
Thyroid hormone receptor (TR) mediates the crucial effects of the thyroid hormone (T3) on cellular growth, development, and differentiation. Decreased expression or inactivating somatic mutations of TRs have been found in human cancers of the liver, breast, lung, and thyroid. The mechanisms of TR-associated carcinogenesis are still not clear. To establish the function of TRβ in thyroid cancer cell proliferation, we constructed a recombinant adenovirus vector, AdTRβ, which expresses human TRβ1 cDNA. Thyroid cancer cell lines in which TRβ protein levels were significantly decreased as compared to intact thyroid tissues were infected with AdTRβ and the function of TRβ on cell proliferation and migration was analyzed. Ligand-bound TRβ induced HDAC1 and HDAC3 dissociation from, and histone acetylation associated with the RhoB promoter and enhanced the expression of RhoB mRNA and protein. In AdTRβ-infected cells, T3 and farnesyl transferase inhibitor (FTI)-treatment induced the distribution of RhoB on the cell membrane and enhanced the abundance of active GTP-bound RhoB. This RhoB protein led to p21-associated cell-cycle arrest in the G0/G1 phase, following inhibition of cell proliferation and invasion. Conversely, lowering cellular RhoB by small interfering RNA knockdown in AdTRβ-infected cells led to downregulation of p21 and inhibited cell-cycle arrest. The growth of BHP18-21v tumor xenografts in vivo was significantly inhibited by AdTRβ injection with FTIs-treatment, as compared to control virus-injected tumors. This novel signaling pathway triggered by ligand-bound TRβ provides insight into possible mechanisms of proliferation and invasion of thyroid cancer and may provide new therapeutic targets for thyroid cancers.
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影响因子：
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通讯作者：
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影响因子：
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作者：
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