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

Krystian Jazdzewski1, Joanna Boguslawska, Jaroslaw Jendrzejewski

  • 1Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, 804 Biomedical Research Tower, 460 West 12th Avenue, Columbus, Ohio 43210, USA. krystian.jazdzewski@osumc.edu

The Journal of Clinical Endocrinology and Metabolism
|December 17, 2010
PubMed
Abstract

Insights

MicroRNAs (miRs) found at higher levels in papillary thyroid carcinoma (PTC) directly suppress thyroid hormone receptor beta (THRB) expression. This finding reveals a novel mechanism in thyroid cancer development and suggests miRs as potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Thyroid hormone receptor beta (THRB) loss is frequent in tumors.
  • Truncated THRB gene expression is linked to thyroid cancer in mouse models.
  • Eight microRNAs (miRs) show increased expression in papillary thyroid carcinoma (PTC) tumors.

Purpose of the Study:

  • To investigate if PTC-upregulated miRs inhibit THRB.
  • To elucidate the regulatory role of specific miRs in thyroid cancer.

Main Methods:

  • In silico analysis of miR binding sites on THRB 3'-UTR.
  • Luciferase assays to confirm direct miR-THRB interaction.
  • Cell line experiments assessing THRB and target gene (DIO1, APP) expression after pre-miR transfection.
  • Promoter assays to evaluate impact on thyroid hormone response element (TRE) activity.
  • Correlation analysis of THRB and miR expression in PTC tumor/normal tissue pairs.

Main Results:

  • THRB possesses binding sites for seven PTC-upregulated miRs; miR-21 and miR-146a directly interact.
  • Transfection with miR-21, -146a, and -221 reduced THRB transcripts (37-48%).
  • THRB protein was suppressed by four miRs (10-28%).
  • DIO1 and APP expression were significantly altered, and TRE activity was affected by four miRs.
  • 11 of 13 PTC tissue pairs showed reduced THRB and increased miR-21, -146a, -181a, and -221 expression.

Conclusions:

  • MicroRNAs upregulated in PTC directly inhibit THRB expression.
  • THRB acts as a tumor suppressor gene in thyroid cancer.
  • These findings highlight a novel mechanism in PTC pathogenesis.

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