Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Via Pansini 5, 80131 Napoli, Italy.
J Clin Endocrinol Metab. 2012 Nov;97(11):E2168-78. doi: 10.1210/jc.2012-1929. Epub 2012 Sep 10.
Thyroid neoplasias of the follicular histotype include the benign follicular adenomas and the malignant follicular carcinomas. Although several genetic lesions have already been described in human thyroid follicular neoplasias, the mechanisms underlying their development are still far from being completely elucidated. MicroRNAs (miRs or miRNAs) have recently emerged as important regulators of gene expression, also playing a key role in the process of carcinogenesis.
The aim of our work has been to identify the miRNAs differentially expressed in human thyroid follicular neoplasias and define their role in thyroid carcinogenesis.
The miRNA expression profile of 10 human thyroid follicular adenomas was compared to that of 10 normal thyroid tissues.
The miRNA expression profiles revealed the down-regulation of let-7a in thyroid follicular adenomas compared to normal thyroid. Then, quantitative RT-PCR analyses validated the microarray data and showed a significantly higher decrease in let-7a expression in follicular carcinomas. Enforced let-7a expression in the follicular thyroid carcinoma cell line WRO induces an epithelial-like phenotype, increases cell adhesion, and decreases cell migration. Conversely, silencing of let-7a in the normal rat thyroid cell line PC Cl 3 has opposite effects. We identified dysadherin (FXYD5), a cell membrane glycoprotein, correlated with tumor progression and invasiveness, as a target of let-7a. Consistently, an inverse correlation between dysadherin and let-7a expression levels was found in human thyroid follicular adenomas and carcinomas.
These results suggest a role of let-7a down-regulation in the development of thyroid neoplasias of the follicular histotype, likely regulating dysadherin protein expression levels.
滤泡状组织类型的甲状腺肿瘤包括良性的滤泡性腺瘤和恶性的滤泡状癌。尽管在人类甲状腺滤泡状肿瘤中已经描述了几种遗传病变，但它们的发展机制仍远未完全阐明。微小 RNA（miRs 或 miRNAs）最近被认为是基因表达的重要调节因子，在致癌过程中也起着关键作用。
我们的工作旨在鉴定在人类甲状腺滤泡状肿瘤中差异表达的 microRNAs，并定义它们在甲状腺癌发生中的作用。
比较 10 例人甲状腺滤泡性腺瘤和 10 例正常甲状腺组织的 microRNA 表达谱。
miRNA 表达谱显示与正常甲状腺相比，甲状腺滤泡性腺瘤中 let-7a 的表达下调。然后，定量 RT-PCR 分析验证了微阵列数据，并显示滤泡状癌中 let-7a 表达明显降低。在滤泡状甲状腺癌细胞系 WRO 中强制表达 let-7a 会诱导上皮样表型，增加细胞黏附，减少细胞迁移。相反，在正常大鼠甲状腺细胞系 PC Cl 3 中沉默 let-7a 则会产生相反的效果。我们鉴定出黏附素（FXYD5），一种细胞膜糖蛋白，与肿瘤进展和侵袭性相关，是 let-7a 的靶标。一致地，在人类甲状腺滤泡状腺瘤和癌中发现黏附素与 let-7a 表达水平呈负相关。
这些结果表明 let-7a 的下调在滤泡状组织类型的甲状腺肿瘤的发展中起作用，可能调节黏附素蛋白的表达水平。
