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Thyroid hormone receptor beta (THRB) is a major target gene for microRNAs deregulated in papillary thyroid carcinoma (PTC).

ABSTRACT: CONTEXT:Loss of the thyroid hormone receptor is common in tumors. In mouse models, a truncated THRB gene leads to thyroid cancer. Previously, we observed up-regulation of the expression of eight microRNAs (miRs) in papillary thyroid carcinoma (PTC) tumors. OBJECTIVE:Our objective was to determine whether THRB might be inhibited by miRs up-regulated in PTC. DESIGN:The potential binding of miR to the 3'-untranslated region of THRB was analyzed in silico. Direct inhibition by miRs binding to the cloned 3'-untranslated region of THRB was evaluated using luciferase assays. Inhibition of endogenous THRB and its target genes (DIO1 and APP) was examined in cell lines transfected by pre-miRs. The impact on thyroid hormone response element (TRE) was evaluated in promoter assays. Correlations between the expression of THRB and miRs was evaluated in 13 PTC tumor/normal tissue pairs. RESULTS:THRB contains binding sites for the top seven miRs up-regulated in PTC (P = 0.0000002). Direct interaction with THRB was shown for miR-21 and miR-146a. We observed lower levels of THRB transcripts in cell lines transfected with miR-21, -146a, and -221 (down-regulation of 37-48%; P < 0.0001), but not with miR-181a. THRB protein was suppressed down to 10-28% by each of four miRs. Concomitant expression of DIO1 and APP was affected (down-regulation of 32-66%, P < 0.0034 and up-regulation of 48-57%, P < 0.0002, respectively). All four miRs affected TRE activity in promoter assays. Down-regulation of luciferase occurred after transfection with pTRE-TK-Luc construct and each of four miRs. The analysis of tumor/normal tissue pairs revealed down-regulation of THRB in 11 of 13 pairs (1.3- to 9.1-fold), and up-regulation of miR-21, -146a, -181a, and -221 in almost all pairs. CONCLUSIONS:MiRs up-regulated in PTC tumors directly inhibit the expression of THRB, an important tumor suppressor gene.

SUBMITTER: Jazdzewski K 

PROVIDER: S-EPMC3047217 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Thyroid hormone receptor beta (THRB) is a major target gene for microRNAs deregulated in papillary thyroid carcinoma (PTC).

Jazdzewski Krystian K   Boguslawska Joanna J   Jendrzejewski Jaroslaw J   Liyanarachchi Sandya S   Pachucki Janusz J   Wardyn Kazimierz A KA   Nauman Alicja A   de la Chapelle Albert A  

The Journal of clinical endocrinology and metabolism 20101215 3

<h4>Context</h4>Loss of the thyroid hormone receptor is common in tumors. In mouse models, a truncated THRB gene leads to thyroid cancer. Previously, we observed up-regulation of the expression of eight microRNAs (miRs) in papillary thyroid carcinoma (PTC) tumors.<h4>Objective</h4>Our objective was to determine whether THRB might be inhibited by miRs up-regulated in PTC.<h4>Design</h4>The potential binding of miR to the 3'-untranslated region of THRB was analyzed in silico. Direct inhibition by  ...[more]

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