Iodide uptake by the thyroid is mediated by the sodium/iodide symporter. Upon iodide uptake, thyroperoxidase catalyzes iodination of tyrosine residues in thyroglobulin, retaining iodide within thyroid follicles. Dedifferentiation-induced loss of these functions in cancers, rendering them unresponsive to radioiodide, occurs with most poorly differentiated and anaplastic tumors. We focused on the histone deacetylase (HDAC) inhibitors (HDACI) as a way to induce differentiation of thyroid cancer cells. We assessed re-expression of thyroid-specific genes mRNA induced by HDACI using quantitative RT-PCR and immunostaining in poorly differentiated papillary and anaplastic thyroid cancer cells. HDACI induced expression of thyroid-specific gene mRNAs and proteins, and accumulation of radioiodide through iodination of generic cellular proteins were detected. HDACI-treated tumors could specifically accumulate (125)I as revealed by imaging experiments and radioiodide concentration in vivo. In an attempt to determine the mechanism by which these gene expressions occurred, we detected the inhibition of protein synthesis by cycloheximide, which up-regulated the expression of thyroperoxidase and thyroglobulin mRNA in HDACI-treated cells and down-regulated that of sodium/iodide symporter mRNA. Together, our results suggest that HDACI-induced expression of thyroid-specific genes, some of which is mediated by some protein synthesis, may contribute to development of novel strategy against thyroid cancer.

Thyrotropin receptor (TSH-R) has been thought to be thyroid-specific, but, by Northern blot analysis, we found that rat adipose tissue expressed TSH-R mRNAs in amounts approaching those in the thyroid. To investigate the function of TSH-R from adipose tissue, we screened a rat fat cell lambda gt11 cDNA library for TSH-R sequences using a 32P-labeled rat thyroid TSH-R cDNA as a probe. Among 10(6) plaques, we obtained four positive clones. Sequencing of these cDNAs has revealed that two of them (F alpha and F beta) contained both initiation and termination codons. Comparison of F alpha with the thyroid TSH-R cDNA sequence revealed that F alpha was almost identical to the thyroid TSH-R, except that nucleotides 1041 and 1277 were changed from A to G and from C to T, respectively. In contrast, we found that F beta contained 21 novel nucleotides between nucleotides 467 and 468 of the thyroid TSH-R cDNA, encoding an additional 7 amino acids. However, when we prepared mRNA from adipose tissue and transcribed it into cDNA, we failed to amplify the F beta type of TSH-R cDNA by polymerase chain reaction, suggesting that F beta mRNAs are rare in the tissue. We then ligated F cDNAs into pSG5 and transfected them with pSV2-neo into Chinese hamster ovary (CHO)-K1 cells. TSH stimulated cAMP formation in CHO-F alpha cells in a manner similar to that in CHO cells transfected with thyroid TSH-R cDNA. In contrast, no increase of cAMP was observed in CHO-F beta cells. IgG from patients with Graves' disease (n = 4) showed thyroid-stimulating antibody activity only in CHO-F alpha cells (1288-4582%). In addition, CHO-F alpha cells and CHO cells transfected with thyroid TSH-R showed similar 125I-TSH binding activity. These results indicate that the fat cell expresses high levels of a TSH-R whose function is indistinguishable from that in the thyroid and suggest that the TSH-R autoantibody plays an important role in the pathogenesis of the extrathyroidal manifestations of Graves' disease.

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Thyrocytes share characteristics with osteoblasts. Cbfa-1 may play a role in calcification processes in human thyroid papillary carcinoma tissues.

To investigate the in vitro effects of cytokines on the growth of human papillary thyroid carcinoma (PTC) cells, we established six new PTC cell lines, designated BHP 5, 14, 15, 17, 18, and 19, from different patients. We studied the antiproliferative actions of cytokines by using BHP cells, NP cells (PTC cell line), and ARO cells (anaplastic thyroid carcinoma cell line). These cells were treated with various concentrations of tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma), interleukin-1 beta (IL-1 beta), and transforming growth factor-beta 1 (TGF beta 1), alone and in combination. Cell proliferation was assessed by [3H]thymidine incorporation and cell number measurement. In BHP cell lines, IFN gamma, IL-1 beta, and TGF beta 1 inhibited [3H]thymidine incorporation and decreased cell number, but TNF alpha stimulated [3H]thymidine incorporation. In NP cells, treatment with each cytokine decreased [3H]thymidine incorporation and cell number. In contrast, the proliferation of ARO cells was either stimulated by or resistant to TNF alpha, IL-1 beta, and TGF beta 1. The effects of these cytokines on [3H]thymidine incorporation were additive in these cell lines. The results suggest that IL-1 beta and TGF beta 1 play a pivotal role in growth inhibition of PTC cells, and the escape from negative control of IL-1 beta and TGF beta 1 may be a step toward anaplastic changes. The additive effects of these cytokines suggest that they act through different pathways.