Let-7a Down-Regulation Plays a Role in Thyroid Neoplasias of Follicular Histotype Affecting Cell Adhesion and Migration through Its Ability to Target the FXYD5 (Dysadherin) Gene

Context: 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. Objective: 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. Design: The miRNA expression profile of 10 human thyroid follicular adenomas was compared to that of 10 normal thyroid tissues. Results: 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. Conclusions: 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. (J Clin Endocrinol Metab 97: E2168-E2178, 2012)