Approximately 35% of follicular thyroid carcinomas harbor a chromosomal translocation that results in expression of a paired box gene 8-peroxisome proliferator-activated receptor γ gene (PPARγ) fusion protein (PPFP). To better understand the oncogenic role of PPFP and its relationship to endogenous PPARγ, we generated a transgenic mouse model that combines Cre-dependent PPFP expression (PPFP;Cre) with homozygous deletion of floxed Pten (PtenFF;Cre), both thyroid specific. Although neither PPFP;Cre nor PtenFF;Cre mice develop thyroid tumors, the combined PPFP;PtenFF;Cre mice develop metastatic thyroid cancer, consistent with patient data that PPFP is occasionally found in benign thyroid adenomas and that PPFP carcinomas have increased phosphorylated AKT/protein kinase B. We then tested the effects of the PPARγ agonist pioglitazone in our mouse model. Pioglitazone had no effect on PtenFF;Cre mouse thyroids. However, the thyroids in pioglitazone-fed PPFP;PtenFF;Cre mice decreased 7-fold in size, and metastatic disease was prevented. Remarkably, pioglitazone caused an adipogenic response in the PPFP;PtenFF;Cre thyroids characterized by lipid accumulation and the induction of a broad array of adipocyte PPARγ target genes. These data indicate that, in the presence of pioglitazone, PPFP has PPARγ-like activity that results in trans-differentiation of thyroid carcinoma cells into adipocyte-like cells. Furthermore, the data predict that pioglitazone will be therapeutic in patients with PPFP-positive carcinomas.

The syndrome of nonthyroidal illness, also known as the sick euthyroid syndrome, is characterized by a low plasma T3 and an "inappropriately normal" plasma thyrotropin in the absence of intrinsic disease of the hypothalamic-pituitary-thyroid axis. The syndrome is due in part to decreased activity of type I iodothyronine 5-deiodinase (5 D-I), the hepatic enzyme that converts thyroxine to T3 and that is induced at the transcriptional level by T3. The hypothesis tested is that cytokines decrease T3 induction of 5 D-I, resulting in decreased T3 production and hence a further decrease in 5 D-I. The proposed mechanism is competition for limiting amounts of nuclear receptor coactivators between the 5 D-I promoter and the promoters of cytokine-induced genes. Using primary cultures of rat hepatocytes, we demonstrate that interleukins 1 and 6 inhibit the Under ordinary circumstances, plasma levels of thyroid hormone are tightly regulated by a homeostatic feedback loop in which hypothalamic thyrotropin-releasing hormone stimulates secretion of TSH 1 by the anterior pituitary, which in turn stimulates secretion of thyroid hormones by the thyroid gland. 3,5,3Ј-triiodothyronine represses the synthesis and secretion of thyrotropin-releasing hormone and TSH to complete the negative feedback loop. However, this regulatory system is perturbed by virtually any medical illness or surgical stress, resulting in what is known as the syndrome of nonthyroidal illness or the sick euthyroid syndrome (for reviews, see Refs. 1 and 2). The characteristic features of this syndrome are a low plasma T3 concentration with an "inappropriately normal" TSH. The syndrome is seen with both acute and chronic illnesses such as trauma, myocardial infarction, infection, malignancy, and renal failure. The more severe the nonthyroidal illness, the more depressed is the T3 level. Hospitalized patients will often have a frankly low TSH, and occasionally the T4 level also is low in very sick individuals. In fact, a correlation exists between the magnitude of the thyroid function test abnormalities and the mortality rate. The thyroid function test abnormalities resolve if the patient recovers from the nonthyroidal illness.The mechanism that underlies the sick euthyroid syndrome is poorly understood but is clearly multifactorial. Both central (pituitary or hypothalamic) and peripheral defects are apparent. The central defect is manifest by abnormally low secretion of TSH in response to low circulating thyroid hormone levels. Multiple peripheral defects in the distribution and metabolism of thyroid hormone have been observed, but perhaps the most important is a decrease in the conversion of T4 to T3 (3, 4). It is estimated that direct thyroidal secretion accounts for only approximately 20% of plasma T3. The majority of plasma T3 derives from thyroxine deiodination, primarily by the hepatocyte enzyme type I iodothyronine 5Ј-deiodinase. The activity of this enzyme is diminished in the sick euthyroid syndrome, thus accounting for the low plasma T3 despite a normal ...

Background and aims: Although peroxisome proliferator activated receptor c (PPARc) agonists have been implicated in differentiation and growth inhibition of cancer cells, the potential therapeutic and chemopreventive effects on gastric cancer are poorly defined. We examined the in vitro and in vivo effects of PPARc ligands on growth of gastric cancer, and the effect of PPARc activation on expression of cyclooxygenase 2 (COX-2) and cancer related genes. Methods: Gastric cell lines (MKN28 and MKN45) were treated with two specific PPARc ligands: ciglitazone and 15-deoxy-D

Approximately 35% of follicular thyroid carcinomas and a small fraction of follicular adenomas are associated with a t(2;3)(q13;p25) chromosomal translocation that fuses paired box gene 8 (PAX8) with the peroxisome proliferator-activated receptor-gamma gene (PPARG), resulting in expression of a PAX8-PPARgamma fusion protein, PPFP. The mechanism by which PPFP contributes to follicular thyroid neoplasia is poorly understood. Therefore, we have created mice with thyroid-specific expression of PPFP. At 1 yr of age, 25% of PPFP mice demonstrate mild thyroid hyperplasia. We bred these mice to mice with thyroid-specific single-allele deletion of the tumor suppressor Pten, denoted ThyPten(+/-). In humans, PTEN deletion is associated with follicular adenomas and carcinomas, and in mice, deletion of one Pten allele causes mild thyroid hyperplasia. We found that PPFP synergizes with ThyPten(+/-) to cause marked thyroid hyperplasia, but carcinomas were not observed. AKT phosphorylation was increased as expected in the ThyPten(+/-) thyroids, and also was increased in the PPFP thyroids and in human PPFP follicular cancers. Staining for the cell cycle marker Ki-67 was increased in the PPFP, ThyPten(+/-), and PPFP;ThyPten(+/-) thyroids compared with wild-type thyroids. Several genes with increased expression in PPFP cancers also were found to be increased in the thyroids of PPFP mice. This transgenic mouse model of thyroidal PPFP expression exhibits properties similar to those of PPFP thyroid cancers. However, the mice develop thyroid hyperplasia, not carcinoma, suggesting that additional events are required to cause follicular thyroid cancer.

The programme provided overall benefits related to school performance, absences, and home environment. In the agricultural area, where fewer resources were available, benefits were fewer and concerns greater. In the industrial area, where education and income were higher, additional benefits related to healthcare use and parents' quality of life were realized.

Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with an average life expectancy of ∼6 months from the time of diagnosis. The genetic and epigenetic changes that underlie this malignancy are incompletely understood. We found that ASH1-like histone lysine methyltransferase (ASH1L) is overexpressed in ATC relative to the much less aggressive and more common differentiated thyroid cancer. This increased expression was due at least in part to reduced levels of microRNA-200b-3p (miR-200b-3p), which represses ASH1L expression, in ATC. Genetic knockout of ASH1L protein expression in ATC cell lines decreased cell growth both in culture and in mouse xenografts. RNA-Seq analysis of ASH1L knockout versus WT ATC cell lines revealed that ASH1L is involved in the regulation of numerous cancer-related genes and gene sets. The pro-oncogenic long noncoding RNA colon cancer-associated transcript 1 (CCAT1) was one of the most highly (approximately 68-fold) down-regulated transcripts in ASH1L knockout cells. Therefore, we investigated CCAT1 as a potential mediator of the growth-inducing activity of ASH1L. Supporting this hypothesis, CCAT1 knockdown in ATC cells decreased their growth rate, and ChIP-Seq data indicated that CCAT1 is likely a direct target of ASH1L's histone methyltransferase activity. These results indicate that ASH1L contributes to the aggressiveness of ATC and suggest that ASH1L, along with its upstream regulator miR-200b-3p and its downstream mediator CCAT1, represents a potential therapeutic target in ATC.

A chromosomal translocation results in production of an oncogenic PAX8-PPARG fusion protein (PPFP) in thyroid carcinomas. PAX8 is a thyroid transcription factor, and PPARG is a transcription factor that plays important roles in adipocytes and macrophages. PPFP retains the DNA binding domains of both proteins; however, the genomic binding sites of PPFP have not been identified, and only limited data exist to characterize gene expression in PPFP thyroid carcinomas. Therefore, the oncogenic function of PPFP is poorly understood. We expressed PPFP in PCCL3 rat thyroid cells and used ChIP-seq to identify PPFP genomic binding sites (PPFP peaks) and RNA-seq to characterize PPFP-dependent gene expression. PPFP peaks (~20,000) include known PAX8 and PPARG binding sites and are enriched with both motifs, indicating that both DNA binding domains are functional. PPFP binds to and regulates many genes involved in cancer-related processes. In PCCL3 thyroid cells, PPFP binds to adipocyte PPARG target genes in preference to macrophage PPARG target genes, consistent with the pro-adipogenic nature of PPFP and its ligand pioglitazone in thyroid cells. PPFP induces oxidative stress in thyroid cells, and pioglitazone increases susceptibility to further oxidative stress. Our data highlight the complexity of PPFP as a transcription factor and the numerous ways that it regulates thyroid oncogenesis.

Essentially all serious illness is associated with a decrease in circulating T(3), a condition known as the nonthyroidal illness syndrome. Substantial evidence suggests that a contributing factor to this syndrome is a cytokine-induced decrease in hepatic type 1 iodothyronine deiodinase (D1), an enzyme that converts T(4) to T(3). The type 1 deiodinase is induced at the transcriptional level by T(3), but illness-associated cytokines block this induction, resulting in decreased T(3) and hence a further decline in D1 expression. We demonstrated that IL-1 blocks the ability of T(3) to induce D1 in rat hepatocyte primary cultures and that forced expression of steroid receptor co- activator 1 (SRC-1) prevents this cytokine effect. This led us to test whether forced hepatic expression of SRC-1 can prevent the nonthyroidal illness syndrome in vivo. Pretreatment of endotoxin-treated mice with an adenovirus that expresses SRC-1, compared with a control adenovirus, prevented the endotoxin-induced decreases in hepatic D1 and plasma T(3). The data suggest that a cytokine-induced defect in T(3) receptor coactivators is an important component of this animal model of nonthyroidal illness and that the syndrome can be overcome by forced expression of the coactivator.