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

Abstract

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.

Integrated bioinformatics analysis reveals that the expression of cathepsin�S is associated with lymph node metastasis and poor prognosis in papillary thyroid cancer

“…Additionally, RUNX2 was enriched in the GO BP terms ‘positive regulation of cell proliferation’ and in the KEGG pathway ‘transcriptional misregulation in cancer’. In agreement with this, previous studies have identified an association between the expression of RUNX2 and thyroid cancer progression ( 36 – 39 ). Therefore, RUNX2 may play an important role in thyroid tumorigenesis.…”

Thyroid hormone receptor beta inhibits the PI3K-Akt-mTOR signaling axis in anaplastic thyroid cancer via genomic mechanisms

“…These factors include members of the nuclear hormone receptor family including estrogen, androgen, and thyroid hormone receptors (11)(12)(13). Our work has demonstrated that thyroid hormone receptor beta (TRβ) acts as a tumor suppressor in ATC through repression of several pathways important for tumor growth (14,15). However, the potential for TRβ to exhibit tumor suppression in ATC by suppressing PI3K is not fully understood.…”

MiR-150 Inhibits Cell Growth In Vitro and In Vivo by Restraining the RAB11A/WNT/β-Catenin Pathway in Thyroid Cancer

“…Some TCs have favorable prognosis, however, aggressive TCs, which were characterized by a less differentiated cellular phenotype and a higher rate of metastasis and cancer-related mortality, have had no effective treatment approach [ 3 ]. While the development and progression of TCs are not completely clear, many genetic factors involved in their onset have been reported [ 4 – 8 ]. Increasing evidence has revealed the involvement of microRNAs (miRNAs) in human malignancies, and a number of important direct miRNAs-mRNAs regulations have been described in TCs [ 9 – 12 ].…”