Family of microRNA-146 Regulates RARβ in Papillary Thyroid Carcinoma

PLoS One. 2016 Mar 24;11(3):e0151968. doi: 10.1371/journal.pone.0151968. eCollection 2016.

Abstract

Retinoic acid is a promising tool in adjuvant cancer therapies, including refractory thyroid cancer, and its biological role is mediated by the retinoic acid receptor beta (RARβ). However, expression of RARβ is lowered in papillary thyroid carcinoma (PTC), contributing to promotion of tumor growth and inefficiency of retinoic acid and radioactive iodine treatment. The causes of aberrant RARB expression are largely unknown. We hypothesized that the culpable mechanisms include the action of microRNAs from the miR-146 family, previously identified as significantly upregulated in PTC tumors. To test this hypothesis, we assessed the expression of RARB as well as miR-146a-5p and miR-146b-5p in 48 PTC tumor/normal tissue pairs by Taqman assay to reveal that the expression of RARB was 3.28-fold decreased, and miR-146b-5p was 28.9-fold increased in PTC tumors. Direct interaction between miRs and RARB was determined in the luciferase assay and further confirmed in cell lines, where overexpression of miR-146a-5p and miR-146b-5p caused a 31% and 33% decrease in endogenous RARB mRNA levels. Inhibition of miR-146a and miR-146b resulted in 62.5% and 45.4% increase of RARB, respectively, and a concomitant decrease in proliferation rates of thyroid cancer cell lines, analyzed in xCELLigence system.We showed that two microRNAs of the miR-146 family directly regulate RARB. Inhibition of miRs resulted in restoration of RARB expression and decreased rates of proliferation of thyroid cancer cells. By restoring RARB levels, microRNA inhibitors may become part of an adjuvant therapy in thyroid cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Base Sequence
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • Carcinoma, Papillary / genetics*
  • Carcinoma, Papillary / pathology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MicroRNAs / genetics*
  • RNA, Messenger / genetics
  • Receptors, Retinoic Acid / genetics*
  • Thyroid Cancer, Papillary
  • Thyroid Gland / metabolism
  • Thyroid Gland / pathology*
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / pathology

Substances

  • 3' Untranslated Regions
  • MIRN146 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta

Grants and funding

This work was supported by: Polish National Science Centre grant 2012/07/N/NZ3/01515 (to AAC) (www.nauka.gov.pl); Ministry of Science and Higher Education grant 0525/IP1/2015/73 (to AW) (www.nauka.gov.pl); Foundation for Polish Science, Programme TEAM 7/2011, co-financed by the European Union European Regional Development Fund (to KJ) (www.fnp.org.pl); The Laboratory of Genomic Medicine participates in Bastion, a programme financed by the European Union (FP7-REGPOT-2012-CT2012-316254-BASTION).