β-Catenin Regulates Deiodinase Levels and Thyroid Hormone Signaling in Colon Cancer Cells
β-Catenin Regulates Deiodinase Levels and Thyroid Hormone Signaling in Colon Cancer Cells
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DOI：
10.1053/j.gastro.2012.06.042
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发表时间：
2012-10-01
期刊：
影响因子：
29.4
通讯作者：
Salvatore, Domenico
中科院分区：
文献类型：
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作者：
Dentice, Monica;Luongo, Cristina;Salvatore, Domenico
背景与目的：β-连环蛋白/T 细胞因子 (TCF) 复合物的激活发生在大多数结肠肿瘤中，其作用与肠上皮细胞的肿瘤表型相关。 3 型脱碘酶 (D3) 是一种使甲状腺激素（3,5,3'三碘甲状腺原氨酸 [T3]）失活的硒酶，经常由肿瘤细胞表达，但人们对其在癌细胞 T3 信号传导调节中的作用知之甚少。方法：我们测量了 6 种结肠癌细胞系和人类肿瘤中的 D3 表达，并将其与 β-连环蛋白/TCF 复合物的活性相关联。我们还确定了 D3 缺失对局部甲状腺激素信号传导和结肠肿瘤发生的影响。结果：我们证明 D3 是 β-连环蛋白/TCF 复合物的直接转录靶标；其在人肠腺瘤和癌中的表达高于健康肠组织。 β-连环蛋白的实验减弱可降低 D3 水平并诱导 2 型脱碘酶（将 3,5,3',5' 四碘甲状腺原氨酸转化为活性 T3 的 D3 拮抗剂），从而增加 T3 依赖性转录。在缺乏 D3 的情况下，过量的 T3 会减少培养细胞和异种移植小鼠模型中的细胞增殖并促进分化。这是通过诱导 Ecadherin 发生的，Ecadherin 将 β-catenin 隔离在质膜上并促进细胞分化。结论：脱碘酶位于 β-连环蛋白和甲状腺激素途径之间的界面。它们对细胞内 T3 浓度的同步调节是一种迄今为止未被认识的途径，通过该途径产生 β-连环蛋白的多重效应，并且可能有针对性地减少 β-连环蛋白在肠细胞中的致癌作用。
BACKGROUND & AIMS: Activation of the beta-catenin/T-cell factor (TCF) complex occurs in most colon tumors, and its actions correlate with the neoplastic phenotype of intestinal epithelial cells. Type 3 deiodinase (D3), the selenoenzyme that inactivates thyroid hormone (3,5,3 ' triiodothyronine [T3]), is frequently expressed by tumor cells, but little is known about its role in the regulation of T3 signaling in cancer cells. METHODS: We measured D3 expression in 6 colon cancer cell lines and human tumors and correlated it with the activity of the beta-catenin/TCF complex. We also determined the effects of D3 loss on local thyroid hormone signaling and colon tumorigenesis. RESULTS: We show that D3 is a direct transcriptional target of the beta-catenin/TCF complex; its expression was higher in human intestinal adenomas and carcinomas than in healthy intestinal tissue. Experimental attenuation of beta-catenin reduced D3 levels and induced type 2 deiodinase (the D3 antagonist that converts 3,5,3 ',5 ' tetraiodothyronine into active T3) thereby increasing T3-dependent transcription. In the absence of D3, excess T3 reduced cell proliferation and promoted differentiation in cultured cells and in xenograft mouse models. This occurred via induction of Ecadherin, which sequestered beta-catenin at the plasma membrane and promoted cell differentiation. CONCLUSIONS: Deiodinases are at the interface between the beta-catenin and the thyroid hormone pathways. Their synchronized regulation of intracellular T3 concentration is a hitherto unrecognized route by which the multiple effects of beta-catenin are generated and may be targeted to reduce the oncogenic effects of beta-catenin in intestinal cells.