Cooperative Subtype Switch of Thyroid Hormone Receptor and Nuclear Receptor Corepressor Related Epithelial–Mesenchymal Transition in Papillary Thyroid Cancer

Abstract

Background and Objectives: Although thyroid hormones affect human cancer progression, the regulatory mechanism of thyroid hormone receptors in carcinogenesis has not been elucidated. This study aimed to evaluate the expression pattern of the thyroid hormone receptor (TR) and its corepressors, and to investigate the clinical and biological functions of TR. Materials and Methods: Transcriptomic and clinical data for thyroid cancer were downloaded from The Cancer Genome Atlas. Paraffin-embedded tissue sections from patients who underwent thyroidectomy were used for immunohistochemistry. BCPAP cells were treated with T3 to investigate the thyroid hormone target genes. Thyroid hormone receptor alpha (THRA) and Thyroid hormone receptor beta (THRB) were knocked down by transient siRNA transfection. Results: THRA and THRB expression was lower in thyroid cancer tissues than in normal tissues. However, strong focal staining of TRβ was observed in the invasive front. High THRB expression was associated with high Silencing Mediator for Retinoid or Thyroid hormone receptor (SMRT) expression, older age, a high MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) score, more aggressive histological subtypes, more frequent extra-thyroidal extension, and advanced TNM stage. THRB expression was positively correlated with Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A), L1 Cell Adhesion Molecule (L1CAM), and Lysyl Oxidase (LOX) expression. Thyroid hormone-induced HIF1A, L1CAM, and LOX upregulation was abolished by siTHRB but not siTHRA in BCPAP cells. High SMRT and high THRB groups (SMRT/THRB) presented more aggressive clinical features and showed an upregulation of HIF1A, L1CAM, and LOX, as well as of epithelial-mesenchymal transition (EMT)-related genes, causing changes in the tumor microenvironment. Conclusion: Cooperative subtype switching from NCOR1/THRA to SMRT/THRB was thus related to aggressive clinical and molecular features, possibly related to EMT and EMT-related tumor microenvironment.