The role of thyroid hormone nuclear receptors in the heart: evidence from pharmacological approaches

This review evaluates the hypothesis that the cardiac effects of amiodarone can be explained—at least partly—by the induction of a local ‘hypothyroid-like condition’ in the heart. Evidence supporting the hypothesis comprises the observation that amiodarone exerts an inhibitory effect on the binding of T3 to thyroid hormone receptors (TR) alpha-1 and beta-1 in vitro, and on the expression of particular T3-dependent genes in vivo. In the heart, amiodarone decreases heart rate and alpha myosin heavy chain expression (mediated via TR alpha-1), and increases sarcoplasmic reticulum calcium-activated ATPase and beta myosin heavy chain expression (mediated via TR beta-1). Recent data show a significant similarity in expression profiles of 8,435 genes in the heart of hypothyroid and amiodarone-treated animals, although similarities do not always exist in transcripts of ion channel genes. Induction of a hypothyroid cardiac phenotype by amiodarone may be advantageous by decreasing energy demands and increasing energy availability

FOXM1 is a molecular determinant of the mitogenic and invasive phenotype of anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is a very aggressive thyroid cancer. forkhead box protein M1 (FOXM1) is a member of the forkhead box family of transcription factors involved in control of cell proliferation, chromosomal stability, angiogenesis, and invasion. Here, we show that FOXM1 is significantly increased in ATCs compared with normal thyroid, well-differentiated thyroid carcinomas (papillary and/or follicular), and poorly differentiated thyroid carcinomas (P=0.000002). Upregulation of FOXM1 levels in ATC cells was mechanistically linked to loss-of-function of p53 and to the hyperactivation of the phosphatidylinositol-3-kinase/AKT/FOXO3a pathway. Knockdown of FOXM1 by RNA interference inhibited cell proliferation by arresting cells in G2/M and reduced cell invasion and motility. This phenotype was associated with decreased expression of FOXM1 target genes, like cyclin B1 (CCNB1), polo-like kinase 1 (PLK1), Aurora B (AURKB), S-phase kinase-associated protein 2 (SKP2), and plasminogen activator, urokinase: uPA (PLAU). Pharmacological inhibition of FOXM1 in an orthotopic mouse model of ATC reduced tumor burden and metastasization. All together, these findings suggest that FOXM1 represents an important player in thyroid cancer progression to the anaplastic phenotype and a potential therapeutic target for this fatal cancer

NR4A3 Immunostain Is a Highly Sensitive and Specific Marker for Acinic Cell Carcinoma in Cytologic and Surgical Specimens

Objectives: Salivary gland acinic cell carcinoma (AciCC) has recognizable cytomorphologic features that can overlap with benign and malignant entities, creating a diagnostic challenge. AciCC harbors a t(4;9) translocation increasing nuclear receptor subfamily 4 group A member 3 (NR4A3) expression, detectable by immunohistochemistry (IHC) on surgical resection (SR). NR4A3 IHC cytology data are limited. Here, we examine NR4A3 IHC on smears, cell blocks (CBs), and SRs of AciCC and its mimickers. Methods: Our cohort comprised AciCC (including high-grade transformation), secretory carcinoma, mucoepidermoid carcinoma (MEC), Warthin tumor, pleomorphic adenoma (PA), cellular PA, carcinoma ex-PA, oncocytic carcinoma, oncocytoma, and nodular oncocytosis. NR4A3 IHC (Santa Cruz Biotechnology and Origene antibodies) was positive if more than 5% tumor cells showed nuclear staining. Results: Among CBs, 90% of AciCC cases and none of the mimickers expressed NR4A3. Among SRs, 100% of AciCC cases showed diffuse NR4A3, whereas one high-grade MEC expressed focal NR4A3. Concordance was 95% with two antibody clones. Sensitivity, specificity, positive predictive value, and negative predictive value were 90%, 100%, 100%, and 94.7% for CBs and 100%, 98.8%, 92.3%, and 100% for SRs, respectively. NR4A3 immunostaining was demonstrable on smears from an AciCC case. Conclusions: NR4A3 IHC can be a robust diagnostic tool to identify AciCC, especially for cytology specimens.http://deepblue.lib.umich.edu/bitstream/2027.42/176224/2/aqab099.pdfPublished versio