Down-regulation of NR4A1 in follicular thyroid carcinomas is restored following lithium treatment.
Down-regulation of NR4A1 in follicular thyroid carcinomas is restored following lithium treatment.
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DOI：
10.1111/j.1365-2265.2008.03349.x
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发表时间：
2009-03
影响因子：
3.2
通讯作者：
Cerutti JM
中科院分区：
文献类型：
--
作者：
Camacho CP;Latini FR;Oler G;Hojaij FC;Maciel RM;Riggins GJ;Cerutti JM
滤泡性甲状腺腺瘤相关转录本的鉴定将有助于更好地了解滤泡性肿瘤的发病机制和进展。使用基因表达的系列分析，我们确定了5个基因，是不存在的恶性滤泡性甲状腺癌（FTC）库，但在滤泡性腺瘤（FTA）和正常甲状腺库中表达。应用真实的时间PCR方法检测了27例正常甲状腺组织、10例甲状腺癌组织、14例甲状腺癌组织和3株甲状腺癌细胞系中NR 4A1的表达。NR4A1可被各种刺激物短暂地增加，包括锂，其被用作甲状腺癌的131I辅助治疗。我们测试了锂是否可以恢复NR4A1表达。测试了可能参与相同信号传导途径的其他基因的表达。为此，以不同浓度（10mM或20mM）和时间（2h和24h）使用锂，并通过定量PCR测试表达水平。我们接下来测试锂是否可以影响细胞生长和凋亡。我们观察到，与正常甲状腺组织和FTA中的表达相比，NR4A1在大多数研究的FTCs中表达不足。我们还发现NR4A1和FOSB基因表达之间呈正相关。在FTC细胞系中，锂诱导NR4A1和FOSB表达，降低CCDN1表达，抑制细胞生长并引发细胞凋亡。NR4A1在大多数FTC中低表达。NR4A1和Wnt通路基因FOSB的表达缺失与恶性程度相关。这与其表达缺失是FTCs转化过程的一部分的假设一致，作为Wnt途径改变的直接或间接结果。锂恢复NR4A1表达，诱导凋亡并降低细胞生长。这些发现可以解释锂治疗作用的可能分子机制。
The identification of follicular thyroid adenoma-associated transcripts will lead to a better understanding of the events involved in pathogenesis and progression of follicular tumors. Using Serial Analysis of Gene Expression, we identified five genes that are absent in a malignant follicular thyroid carcinoma (FTC) library, but expressed in follicular adenoma (FTA) and normal thyroid libraries. NR4A1, one of the five genes, was validated in a set of 27 normal thyroid tissues, 10 FTAs and 14 FTCs and three thyroid carcinoma cell lines by real time PCR. NR4A1 can be transiently increased by a variety of stimuli, including lithium, which is used as adjuvant therapy of thyroid carcinoma with 131I. We tested if lithium could restore NR4A1 expression. The expression of other genes potentially involved in the same signaling pathway was tested. To this end, lithium was used at different concentration (10mM or 20mM) and time (2h and 24 h) and the level of expression was tested by quantitative PCR. We next tested if Lithium could affect cell growth and apoptosis. We observed that NR4A1 expression was under-expressed in most of the FTCs investigated, compared to expression in normal thyroid tissues and FTAs. We also found a positive correlation between NR4A1 and FOSB gene expression. Lithium induced NR4A1 and FOSB expression, reduced CCDN1 expression, inhibited cell growth and triggered apoptosis in a FTC cell line. NR4A1 is under-expressed in most of FTCs. The loss of expression of both NR4A1 and the Wnt pathway gene FOSB was correlated with malignancy. This is consistent with the hypothesis that its loss of expression is part of the transformation process of FTCs, either as a direct or indirect consequence of Wnt pathway alterations. Lithium restores NR4A1 expression, induces apoptosis and reduces cell growth. These findings may explain a possible molecular mechanism of lithium’s therapeutic action.
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影响因子：
5.4
作者：
Cerutti, JM;Ebina, KN;Kimura, ET
通讯作者：
Kimura, ET
影响因子：
2.1
作者：
Fujii, Yasushi;Matsuda, Satoshi;Koyasu, Shigeo
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影响因子：
6.1
作者：
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通讯作者：
Osmak, M.
影响因子：
3.9
作者：
Latini, Flavia R. M.;Hemerly, Jefferson P.;Cerutti, Janete M.
通讯作者：
Cerutti, Janete M.
影响因子：
3.8
作者：
Kappes, Ashley;Vaccaro, Abram;Chen, Herbert
通讯作者：
Chen, Herbert