Thyroid Hormone Receptor-? (TR?) 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)? is common in human cancers. Restoration of functional TR? delays tumor progression in models of thyroid and breast cancers implicating TR? 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 TR? 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; TR? 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 TR? by small interfering RNA knockdown resulted in a corresponding increase in Runx2 and Runx2-regulated genes, indicating that TR? levels directly impact Runx2 expression and associated epithelial to mesenchymal transition molecules. TR? specifically bound to 3 putative thyroid hormone-response element motifs within the Runx2-P1 promoter ((-)105/(+)133) as detected by EMSA and chromatin immunoprecipitation. TR? suppressed Runx2 transcriptional activities, thus confirming TR? regulation of Runx2 at functional thyroid hormone-response elements. Significantly, these findings indicate that a ratio of the tumor-suppressor TR? and tumor-promoting Runx2 may reflect tumor aggression and serve as biomarkers in biopsy tissues. The discovery of this TR?-Runx2 signaling supports the emerging role of TR? as a tumor suppressor and reveals a novel pathway for intervention.

SUBMITTER: Carr FE 

PROVIDER: S-EPMC4967127 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature