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

摘要

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