Data from Thyroid Hormone Regulation of miR-21 Enhances Migration and Invasion of Hepatoma

Abstract

<div>Abstract<p>Thyroid hormone (T<sub>3</sub>) signaling through the thyroid hormone receptor (TRα1) regulates hepatoma cell growth and pathophysiology, but the underlying mechanisms are unclear at present. Here, we have shown that the oncomir microRNA-21 (<i>miR-21</i>) is activated by T<sub>3</sub> through a native T<sub>3</sub> response element in the primary <i>miR-21</i> promoter. Overexpression of <i>miR-21</i> promoted hepatoma cell migration and invasion, similar to that observed with T<sub>3</sub> stimulation in hepatoma cells. In addition, anti-<i>miR-21</i>–induced suppression of cell migration was rescued by T<sub>3</sub>. The Rac-controlled regulator of invasion and metastasis, T-cell lymphoma invasion and metastasis 1 (TIAM1), was identified as a <i>miR-21</i> target additionally downregulated by T<sub>3</sub>. Attenuation and overexpression of <i>miR-21</i> induced upregulation and downregulation of TIAM1, respectively. TIAM1 attenuation, in turn, enhanced migration and invasion via the upregulation of β-catenin, vimentin, and matrix metalloproteinase-2 in hepatoma cells. Notably, correlations between TRα1, <i>miR-21</i>, and TIAM1 expression patterns in animal models paralleled those observed <i>in vitro</i>. In the clinic, we observed a positive correlation (<i>P</i> = 0.005) between the tumor/nontumor ratios of <i>TRα1</i> and <i>miR-21</i> expression, whereas a negative correlation (<i>P</i> = 0.019) was seen between <i>miR-21</i> and <i>TIAM1</i> expression in patients with hepatoma. Our findings collectively indicate that <i>miR-21</i> stimulation by T<sub>3</sub> and subsequent TIAM1 suppression promotes hepatoma cell migration and invasion. <i>Cancer Res; 73(8); 2505–17. ©2013 AACR</i>.</p></div>