Abstract
Thyroid hormone (T(3)) 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 (miR-21) is activated by T(3) through a native T(3) response element in the primary miR-21 promoter. Overexpression of miR-21 promoted hepatoma cell migration and invasion, similar to that observed with T(3) stimulation in hepatoma cells. In addition, anti-miR-21-induced suppression of cell migration was rescued by T(3). The Rac-controlled regulator of invasion and metastasis, T-cell lymphoma invasion and metastasis 1 (TIAM1), was identified as a miR-21 target additionally downregulated by T(3). Attenuation and overexpression of miR-21 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, miR-21, and TIAM1 expression patterns in animal models paralleled those observed in vitro. In the clinic, we observed a positive correlation (P = 0.005) between the tumor/nontumor ratios of TRα1 and miR-21 expression, whereas a negative correlation (P = 0.019) was seen between miR-21 and TIAM1 expression in patients with hepatoma. Our findings collectively indicate that miR-21 stimulation by T(3) and subsequent TIAM1 suppression promotes hepatoma cell migration and invasion.
Highlights
The thyroid hormone (T3) is an important regulator of growth, development, and differentiation in vertebrates
As miR-21 is upregulated by T3, we further examined whether T-cell lymphoma invasion and metastasis 1 (TIAM1) 30 untranslated region (30UTR) luciferase activity is affected by the T3
T3/thyroid hormone receptor signaling promotes cell invasiveness involved in hepatoma progression through the direct or indirect upregulation of several genes, including furin [10], methionine adenosyltransferase 1A [9], plasminogen activator inhibitor-1 [18], and TNF-related apoptosis-inducing ligand [19]
Summary
The thyroid hormone (T3) is an important regulator of growth, development, and differentiation in vertebrates. T3 binds to thyroid hormone receptors that belong to the nuclear receptor superfamily. Human thyroid hormone receptors are encoded by TRa and TRb genes located on chromosomes 17 and 3, respectively. The 2 genes yield several polypeptides via alternative splicing and differential promoter usage. The TRa1, TRb1, and TRb2 genes encoding functional products have been well characterized. Accumulating evidence supports a critical role of thyroid hormone receptors in carcinogenesis.
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