microRNAs 424 and 503 are mediators of the anti-proliferative and anti-invasive action of the thyroid hormone receptor beta
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Lidia Ruiz-Llorente, Soraya Ardila-González, Luisa F Fanjul, Olaia Martínez-Iglesias, Ana Aranda
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain
Ana Aranda, e-mail: firstname.lastname@example.org
Keywords: thyroid hormone receptor, microRNA-424, microRNA-503, proliferation, invasion, hepatocarcinoma and breast cancer cells
Received: November 05, 2013 Accepted: March 27, 2014 Published: April 02, 2014
Abbreviations: HAT, histone acetyltransferase; T3, triiodothyronine; TRb, thyroid hormone receptor beta; SK-TRb, SK-hep1 cells stably expressing the TRb isoform, MDA-TRb, MDA-MB-468 cells stably expressing TRb.
The thyroid hormone receptors (TRs) mediate tumor suppressive effects in hepatocarcinoma and breast cancer cells. Here we show that incubation of hepatocarcinoma SK-hep1 cells expressing TRb with the thyroid hormone T3 induces transcription of the polycistronic message coding for microRNAs 424 and 503. TRb binds to the promoter region of these miRNAs and T3 induces an exchange of corepressors and coactivators inducing histone acetylation and transcriptional stimulation. We have validated cell cycle components as targets of these miRNAs. Overexpression of miR-424 mimicked the repressive effect of T3 on cell proliferation, growth in suspension, migration and invasion. Knockdown of miR-424 or miR-503 reduced the inhibitory effect of the hormone. T3 increased miR-424 and miR-503 in breast cancer cells expressing TRb, and this induction is also involved in the anti-invasive effects of the hormone. Furthermore, miR-424 or miR-503 depletion enhanced extravasation to the lungs of hepatocarcinoma cells injected in the tail vein of mice. The levels of these miRNAs were reduced in xenograft tumors formed in hypothyroid nude mice that are more invasive. Therefore, miR-424 or miR-503 mediate anti-proliferative and anti-invasive actions of TRb both in cultured cells and in vivo.
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