Thyroid Hormone Receptor-β (TRβ) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A Novel Signaling Pathway in Thyroid Cancer

Endocrinology. 2016 Aug;157(8):3278-92. doi: 10.1210/en.2015-2046. Epub 2016 Jun 2.


Dysregulation of the thyroid hormone receptor (TR)β is common in human cancers. Restoration of functional TRβ delays tumor progression in models of thyroid and breast cancers implicating TRβ as a tumor suppressor. Conversely, aberrant expression of the runt-related transcription factor 2 (Runx2) is established in the progression and metastasis of thyroid, breast, and other cancers. Silencing of Runx2 diminishes tumor invasive characteristics. With TRβ as a tumor suppressor and Runx2 as a tumor promoter, a compelling question is whether there is a functional relationship between these regulatory factors in thyroid tumorigenesis. Here, we demonstrated that these proteins are reciprocally expressed in normal and malignant thyroid cells; TRβ is high in normal cells, and Runx2 is high in malignant cells. T3 induced a time- and concentration-dependent decrease in Runx2 expression. Silencing of TRβ by small interfering RNA knockdown resulted in a corresponding increase in Runx2 and Runx2-regulated genes, indicating that TRβ levels directly impact Runx2 expression and associated epithelial to mesenchymal transition molecules. TRβ specifically bound to 3 putative thyroid hormone-response element motifs within the Runx2-P1 promoter ((-)105/(+)133) as detected by EMSA and chromatin immunoprecipitation. TRβ suppressed Runx2 transcriptional activities, thus confirming TRβ regulation of Runx2 at functional thyroid hormone-response elements. Significantly, these findings indicate that a ratio of the tumor-suppressor TRβ and tumor-promoting Runx2 may reflect tumor aggression and serve as biomarkers in biopsy tissues. The discovery of this TRβ-Runx2 signaling supports the emerging role of TRβ as a tumor suppressor and reveals a novel pathway for intervention.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Core Binding Factor Alpha 1 Subunit / genetics*
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Promoter Regions, Genetic / drug effects
  • Response Elements
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Thyroid Gland / metabolism
  • Thyroid Hormone Receptors beta / physiology*
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / metabolism
  • Transcriptional Activation / drug effects
  • Triiodothyronine / pharmacology


  • Core Binding Factor Alpha 1 Subunit
  • RUNX2 protein, human
  • Thyroid Hormone Receptors beta
  • Triiodothyronine