Publications by authors named "Ronald J Koenig"

47 Publications

Novel role of ASH1L histone methyltransferase in anaplastic thyroid carcinoma.

J Biol Chem 2020 06 12;295(26):8834-8845. Epub 2020 May 12.

Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA

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 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.
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http://dx.doi.org/10.1074/jbc.RA120.013530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324504PMC
June 2020

The transcription factor NKX1-2 promotes adipogenesis and may contribute to a balance between adipocyte and osteoblast differentiation.

J Biol Chem 2019 11 15;294(48):18408-18420. Epub 2019 Oct 15.

Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109

Although adipogenesis is mainly controlled by a small number of master transcription factors, including CCAAT/enhancer-binding protein family members and peroxisome proliferator-activated receptor γ (PPARγ), other transcription factors also are involved in this process. Thyroid cancer cells expressing a paired box 8 (PAX8)-PPARγ fusion oncogene trans-differentiate into adipocyte-like cells in the presence of the PPARγ ligand pioglitazone, but this trans-differentiation is inhibited by the transcription factor NK2 homeobox 1 (NKX2-1). Here, we tested whether NKX family members may play a role also in normal adipogenesis. Using quantitative RT-PCR (RT-qPCR), we examined the expression of all 14 NKX family members during 3T3-L1 adipocyte differentiation. We found that most NKX members, including NKX2-1, are expressed at very low levels throughout differentiation. However, mRNA and protein expression of a related family member, NKX1-2, was induced during adipocyte differentiation. NKX1-2 also was up-regulated in cultured murine ear mesenchymal stem cells (EMSCs) during adipogenesis. Importantly, shRNA-mediated NKX1-2 knockdown in 3T3-L1 preadipocytes or EMSCs almost completely blocked adipocyte differentiation. Furthermore, NKX1-2 overexpression promoted differentiation of the ST2 bone marrow-derived mesenchymal precursor cell line into adipocytes. Additional findings suggested that NKX1-2 promotes adipogenesis by inhibiting expression of the antiadipogenic protein COUP transcription factor II. Bone marrow mesenchymal precursor cells can differentiate into adipocytes or osteoblasts, and we found that NKX1-2 both promotes ST2 cell adipogenesis and inhibits their osteoblastogenic differentiation. These results support a role for NKX1-2 in promoting adipogenesis and possibly in regulating the balance between adipocyte and osteoblast differentiation of bone marrow mesenchymal precursor cells.
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http://dx.doi.org/10.1074/jbc.RA119.007967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885646PMC
November 2019

Rare Clinical Entity: Metastatic malignant struma ovarii diagnosed during pregnancy - Lessons for management.

Clin Diabetes Endocrinol 2018 19;4:13. Epub 2018 Jun 19.

4Department of Nuclear Medicine, University of Michigan, 1500 E Medical Center Dr, B1G505, Ann Arbor, MI 48109-5028 USA.

Background: Malignant struma ovarii is an ovarian teratoma containing at least 50% thyroid tissue which has the potential to metastasize and produce thyroid hormone. Given its rarity, management strategies are not well-established. We report a case of metastatic malignant struma ovarii discovered during pregnancy with lessons for evaluation and management.

Case Presentation: A 30-year-old woman who was two months pregnant was discovered to have struma ovarii with over half of the struma comprised of papillary thyroid cancer. Following tumor resection, delivery, and thyroidectomy, she underwent evaluation with stimulated thyroglobulin testing and diagnostic staging sodium iodide-131 scan (I-131), which revealed the presence of skeletal metastases. Following administration of 320 mCi I-131, post-therapy scan also showed miliary pulmonary metastases with improved ability to localize the bony and pulmonary metastases with concurrent SPECT/CT imaging. A second dosimetry-guided I-131 therapy resulted in complete resolution of pulmonary metastases; however, small foci of residual bone disease persisted. Post-therapy scans demonstrated additional findings not shown on diagnostic I-131 scans obtained prior to both her initial and second I-131 therapy.

Conclusions: SPECT/CT provides accurate anatomic correlation and localization of metastatic foci and can serve as a baseline study to assess interval response to treatment. Post-therapy scans should always be obtained when I-131 treatment is administered, as additional findings may be revealed versus low dose I-131 activity diagnostic scans. This patient had a high metastatic burden that would not have been discovered in a timely fashion with the conservative approach advocated by others. Thyroidectomy followed by a diagnostic staging radioiodine scan and a stimulated thyroglobulin level should be considered in patients with malignant struma ovarii for guiding therapeutic I-131 administration as metastatic risk is difficult to predict based on histopathologic examination.
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http://dx.doi.org/10.1186/s40842-018-0064-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006564PMC
June 2018

Fibroblast Growth Factor 23-Induced Hypophosphatemia in Acute Leukemia.

J Endocr Soc 2018 May 6;2(5):437-443. Epub 2018 Apr 6.

Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

Fibroblast growth factor 23 (FGF23)-induced hypophosphatemia is a rare paraneoplastic syndrome of phosphate wasting that, if unrecognized, may cause tumor-induced osteomalacia. It is classically associated with benign mesenchymal tumors but occasionally has been found in patients with other malignancies. Hypophosphatemia has been associated with acute leukemia but has not previously been reported to be due to inappropriate FGF23 secretion. Here, we describe FGF23-induced severe hypophosphatemia and renal phosphate wasting associated with a mixed-phenotype Philadelphia chromosome-like acute leukemia in a previously healthy 22-year-old man. He was found to have low serum 1,25-dihydroxyvitamin D and extremely high FGF23 levels, as well as inappropriate urinary phosphorus excretion. The hypophosphatemia improved with calcitriol and oral phosphate treatment but normalized only during chemotherapy-induced ablation of the blasts. FGF23 levels declined with a reduction in peripheral blast counts. Using real-time reverse transcription polymerase chain reaction, we found that the leukemia cells were the source of FGF23. To our knowledge, this is the first description of FGF23-induced hypophosphatemia associated with acute leukemia. We recommend that the FGF23 paraneoplastic syndrome be considered as a possible etiology of hypophosphatemia in patients with acute leukemia.
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http://dx.doi.org/10.1210/js.2018-00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912090PMC
May 2018

Thyroid-Specific PPARγ Deletion Is Benign in the Mouse.

Endocrinology 2018 03;159(3):1463-1468

Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan.

Peroxisome proliferator-activated receptor γ (PPARγ) is widely expressed at low levels and regulates many physiological processes. In mice and humans, there is evidence that PPARγ can function as a tumor suppressor. A PAX8-PPARγ fusion protein (PPFP) is oncogenic in a subset of thyroid cancers, suggesting that inhibition of endogenous PPARγ function by the fusion protein could contribute to thyroid oncogenesis. However, the function of PPARγ within thyrocytes has never been directly tested. Therefore, we have created a thyroid-specific genetic knockout of murine Pparg and have studied thyroid biology in these mice. Thyroid size and histology, the expression of thyroid-specific genes, and serum T4 levels all are unaffected by loss of thyroidal PPARγ expression. PPFP thyroid cancers have increased activation of AKT, and mice with thyroid-specific expression of PPFP combined with thyroid-specific loss of PTEN (a negative regulator of AKT) develop thyroid cancer. Therefore we created mice with combined thyroid-specific deletions of Pparg and Pten to test if there is oncogenic synergy between these deletions. Pten deletion alone results in benign thyroid hyperplasia, and this is unchanged when combined with deletion of Pparg. We conclude that, at least in the contexts studied, thyrocyte PPARγ does not play a significant role in the development or function of the thyroid and does not function as a tumor suppressor.
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http://dx.doi.org/10.1210/en.2017-03163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839734PMC
March 2018

Pioglitazone Therapy of PAX8-PPARγ Fusion Protein Thyroid Carcinoma.

J Clin Endocrinol Metab 2018 04;103(4):1277-1281

Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

Context: A subset of thyroid carcinomas expresses an oncogenic paired box 8 (PAX8) and peroxisome proliferator activated receptor γ (PPARγ) fusion protein (PPFP). The PPARγ/PPFP ligand pioglitazone is highly therapeutic in a transgenic mouse model of PPFP thyroid carcinoma, but whether pioglitazone is therapeutic in patients with PPFP thyroid carcinoma is unknown.

Case Description: Tumor blocks from 40 patients with progressive thyroid cancer despite standard-of-care therapy were screened for PPFP, and the tumor from only one patient (2.5%) was positive. The patient had a 6.0-cm acetabular soft tissue metastasis from Hürthle cell carcinoma that caused severe pain on weight bearing and had a serum thyroglobulin level of 1974 ng/mL. After 24 weeks of therapy with pioglitazone, the metastatic lesion was 3.9 cm, the thyroglobulin level was 49.4 ng/mL, and the patient was pain-free. Thirteen months after discontinuation of pioglitazone, the metastatic lesion was 3.6 cm, the thyroglobulin level was 4.7 ng/mL, and the patient remained pain-free.

Conclusions: Pioglitazone may be therapeutic in patients with PPFP thyroid cancer. However, thyroid cancers that are progressive despite standard-of-care therapy appear to only rarely express PPFP.
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http://dx.doi.org/10.1210/jc.2017-02533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456920PMC
April 2018

Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer.

Oncotarget 2017 Jan;8(4):5761-5773

Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

PAX8-PPARG fusion protein (PPFP) results from a t(2;3)(q13;p25) chromosomal translocation, is found in 30% of follicular thyroid carcinomas, and demonstrates oncogenic capacity in transgenic mice. A PPARG ligand, pioglitazone, is highly therapeutic in mice with PPFP thyroid cancer. However, only limited data exist to characterize the binding sites and oncogenic function of PPFP, or to explain the observed therapeutic effect of pioglitazone. Here we used our previously characterized transgenic mouse model of PPFP follicular thyroid carcinoma to identify PPFP binding sites in vivo using ChIP-seq, and to distinguish genes and pathways regulated directly or indirectly by PPFP with and without pioglitazone treatment via integration with RNA-seq data. PPFP bound to DNA regions containing the PAX8 and/or the PPARG motif, near genes involved in lipid metabolism, the cell cycle, apoptosis, and cell motility; the binding site distribution was highly concordant with our previous study in a rat PCCL3 cell line. Most strikingly, pioglitazone induced an immune cell infiltration including macrophages and T cells only in the presence of PPFP, which may be central to its therapeutic effect.
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http://dx.doi.org/10.18632/oncotarget.14050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351587PMC
January 2017

LncRNA SRA promotes hepatic steatosis through repressing the expression of adipose triglyceride lipase (ATGL).

Sci Rep 2016 10 19;6:35531. Epub 2016 Oct 19.

Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, 140 Hanzhong Rd., Nanjing, Jiangsu, 210029, China.

Nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, manifests as an over-accumulation of hepatic fat. We have recently shown that mice with genetic knockout of a long non-coding RNA (lncRNA) steroid receptor RNA activator (SRA) (SRAKO) are resistant to high fat diet-induced obesity with a phenotype that includes improved glucose tolerance and attenuated hepatic steatosis. The underlying mechanism was investigated in the present study. We found that hepatic levels of SRA and adipose triglyceride lipase (ATGL), a major hepatic triacylglycerol (TAG) hydrolase, were inversely regulated by fasting in mice, and the expression of liver ATGL was induced by SRAKO under normal and high fat diet (HFD) feeding. Loss of SRA in primary hepatocytes or a hepatocyte cell line upregulates, but forced expression of SRA inhibits ATGL expression and free fatty acids (FFA) β-oxidation. SRA inhibits ATGL promoter activity, primarily by inhibiting the otherwise-inductive effects of the transcription factor, forkhead box protein O1 (FoxO1). Our data reveal a novel function of SRA in promoting hepatic steatosis through repression of ATGL expression.
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http://dx.doi.org/10.1038/srep35531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069493PMC
October 2016

Adipogenic Differentiation of Thyroid Cancer Cells Through the Pax8-PPARγ Fusion Protein Is Regulated by Thyroid Transcription Factor 1 (TTF-1).

J Biol Chem 2016 09 19;291(37):19274-86. Epub 2016 Jul 19.

From the Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109-5678 and.

A subset of thyroid carcinomas contains a t(2;3)(q13;p25) chromosomal translocation that fuses paired box gene 8 (PAX8) with the peroxisome proliferator-activated receptor γ gene (PPARG), resulting in expression of a PAX8-PPARγ fusion protein, PPFP. We previously generated a transgenic mouse model of PPFP thyroid carcinoma and showed that feeding the PPARγ agonist pioglitazone greatly decreased the size of the primary tumor and prevented metastatic disease in vivo The antitumor effect correlates with the fact that pioglitazone turns PPFP into a strongly PPARγ-like molecule, resulting in trans-differentiation of the thyroid cancer cells into adipocyte-like cells that lose malignant character as they become more differentiated. To further study this process, we performed cell culture experiments with thyrocytes from the PPFP mouse thyroid cancers. Our data show that pioglitazone induced cellular lipid accumulation and the expression of adipocyte marker genes in the cultured cells, and shRNA knockdown of PPFP eliminated this pioglitazone effect. In addition, we found that PPFP and thyroid transcription factor 1 (TTF-1) physically interact, and that these transcription factors bind near each other on numerous target genes. TTF-1 knockdown and overexpression studies showed that TTF-1 inhibits PPFP target gene expression and impairs adipogenic trans-differentiation. Surprisingly, pioglitazone repressed TTF-1 expression in PPFP-expressing thyrocytes. Our data indicate that TTF-1 interacts with PPFP to inhibit the pro-adipogenic response to pioglitazone, and that the ability of pioglitazone to decrease TTF-1 expression contributes to its pro-adipogenic action.
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http://dx.doi.org/10.1074/jbc.M116.740324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016669PMC
September 2016

Genomic binding and regulation of gene expression by the thyroid carcinoma-associated PAX8-PPARG fusion protein.

Oncotarget 2015 Dec;6(38):40418-32

Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

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.
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http://dx.doi.org/10.18632/oncotarget.6340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747342PMC
December 2015

Clinical case seminar: unraveling the mystery of abnormal thyroid function tests.

Clin Diabetes Endocrinol 2015 11;1:14. Epub 2015 Sep 11.

Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI USA.

A 53 year old woman was referred to us because of large goiter, enlarged pituitary and grossly elevated TSH and free T4. The differential diagnosis included a TSH producing adenoma vs. artifactual laboratory tests. A careful step-by step analysis of different possibilities allowed correct diagnosis and treatment.
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http://dx.doi.org/10.1186/s40842-015-0010-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471849PMC
September 2015

Identification of the Genomic Insertion Site of the Thyroid Peroxidase Promoter-Cre Recombinase Transgene Using a Novel, Efficient, Next-Generation DNA Sequencing Method.

Thyroid 2015 Oct 7;25(10):1162-6. Epub 2015 Aug 7.

1 Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan , Ann Arbor, Michigan.

Background: It can be useful to know the transgene insertion site in transgenic mice for a variety of reasons, but determining the insertion site generally is a time consuming, expensive, and laborious task.

Methods: A simple method is presented to determine transgene insertion sites that combines the enrichment of a sequencing library by polymerase chain reaction (PCR) for sequences containing the transgene, followed by next-generation sequencing of the enriched library. This method was applied to determine the site of integration of the thyroid peroxidase promoter-Cre recombinase mouse transgene that is commonly used to create thyroid-specific gene deletions.

Results: The insertion site was found to be between bp 12,372,316 and 12,372,324 on mouse chromosome 9, with the nearest characterized genes being Cntn5 and Jrkl, ∼1.5 and 0.9 Mbp from the transgene, respectively. One advantage of knowing a transgene insertion site is that it facilitates distinguishing hemizygous from homozygous transgenic mice. Although this can be accomplished by real-time quantitative PCR, the expected Ct difference is only one cycle, which is challenging to assess accurately. Therefore, the transgene insertion site information was used to develop a 3-primer qualitative PCR assay that readily distinguishes wild type, hemizygous, and homozygous TPO-Cre mice based upon size differences of the wild type and transgenic allele PCR products.

Conclusions: Identification of the genomic insertion site of the thyroid peroxidase promoter-Cre mouse transgene should facilitate the use of these mice in studies of thyroid biology.
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http://dx.doi.org/10.1089/thy.2015.0215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589305PMC
October 2015

Pax-8-PPAR-γ fusion protein in thyroid carcinoma.

Nat Rev Endocrinol 2014 Oct 29;10(10):616-23. Epub 2014 Jul 29.

Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 5560 MSRB-2, SPC 5678, 1150 West Medical Drive, Ann Arbor, MI 48109, USA.

Thyroid carcinoma is the most common endocrine malignancy, and its incidence is continuing to increase. Most thyroid carcinomas contain one of several known driver mutations, such as the Val600Glu substitution in B-Raf, Ras mutations, RET gene fusions, or PAX8-PPARG gene fusions. The PAX8-PPARG gene fusion results in the production of a Pax-8-PPAR-γ fusion protein (PPFP), which is found in approximately one-third of follicular thyroid carcinomas, as well as some follicular-variant papillary thyroid carcinomas. In vitro and in vivo evidence indicates that PPFP is an oncoprotein. Although specific mechanisms of action remain to be defined, PPFP is considered to act as a dominant-negative inhibitor of wild-type PPAR-γ and/or as a unique transcriptional activator of subsets of PPAR-γ-responsive and Pax-8-responsive genes. Detection of the fusion transcript in thyroid nodule biopsy specimens can aid clinical decision-making when cytological findings are indeterminate. The PPAR-γ agonist pioglitazone is highly therapeutic in a transgenic mouse model of PPFP-positive thyroid carcinoma, suggesting that PPAR-γ agonists might be beneficial in patients with PPFP-positive thyroid carcinomas.
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http://dx.doi.org/10.1038/nrendo.2014.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290886PMC
October 2014

SRA regulates adipogenesis by modulating p38/JNK phosphorylation and stimulating insulin receptor gene expression and downstream signaling.

PLoS One 2014 17;9(4):e95416. Epub 2014 Apr 17.

Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.

The Steroid Receptor RNA Activator (SRA) enhances adipogenesis and increases both glucose uptake and phosphorylation of Akt and FOXO1 in response to insulin. To assess the mechanism, we differentiated ST2 mesenchymal precursor cells that did or did not overexpress SRA into adipocytes using combinations of methylisobutylxanthine, dexamethasone and insulin. These studies showed that SRA overexpression promotes full adipogenesis in part by stimulation of insulin/insulin-like growth factor-1 (IGF-1) signaling. SRA overexpression inhibited phosphorylation of p38 mitogen activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) in the early differentiation of ST2 cells. Conversely, knockdown of endogenous SRA in 3T3-L1 cells increased phosphorylation of JNK. Knockdown of SRA in mature 3T3-L1 adipocytes reduced insulin receptor (IR) mRNA and protein levels, which led to decreased autophosphorylation of IRβ and decreased phosphorylation of insulin receptor substrate-1 (IRS-1) and Akt. This likely reflects a stimulatory role of SRA on IR transcription, as transfection studies showed that SRA increased expression of an IR promoter-luciferase reporter construct.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095416PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990642PMC
June 2015

SRA gene knockout protects against diet-induced obesity and improves glucose tolerance.

J Biol Chem 2014 May 27;289(19):13000-9. Epub 2014 Mar 27.

From the Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes.

We have recently shown that the non-coding RNA, steroid receptor RNA activator (SRA), functions as a transcriptional coactivator of PPARγ and promotes adipocyte differentiation in vitro. To assess SRA function in vivo, we have generated a whole mouse Sra1 gene knock-out (SRA(-/-)). Here, we show that the Sra1 gene is an important regulator of adipose tissue mass and function. SRA is expressed at a higher level in adipose tissue than other organs in wild type mice. SRA(-/-) mice are resistant to high fat diet-induced obesity, with decreased fat mass and increased lean content. This lean phenotype of SRA(-/-) mice is associated with decreased expression of a subset of adipocyte marker genes and reduced plasma TNFα levels. The SRA(-/-) mice are more insulin sensitive, as evidenced by reduced fasting insulin, and lower blood glucoses in response to IP glucose and insulin. In addition, the livers of SRA(-/-) mice have fewer lipid droplets after high fat diet feeding, and the expression of lipogenesis-associated genes is decreased. To our knowledge, these data are the first to indicate a functional role for SRA in adipose tissue biology and glucose homeostasis in vivo.
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http://dx.doi.org/10.1074/jbc.M114.564658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036315PMC
May 2014

The thyroid cancer PAX8-PPARG fusion protein activates Wnt/TCF-responsive cells that have a transformed phenotype.

Endocr Relat Cancer 2013 Oct 11;20(5):725-39. Epub 2013 Sep 11.

Cellular and Molecular Biology Graduate Program, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, 48109, USA.

A chromosomal translocation results in the production of a paired box 8-peroxisome proliferator-activated receptor gamma (PAX8-PPARG) fusion protein (PPFP) in ∼35% of follicular thyroid carcinomas. To examine the role of PPFP in thyroid oncogenesis, the fusion protein was stably expressed in the non-transformed rat thyroid cell line PCCL3. PPFP conferred on PCCL3 cells the ability to invade through Matrigel and to form colonies in anchorage-independent conditions. PPFP also increased the fraction of cells with Wnt/TCF-responsive green fluorescent protein reporter gene expression. This Wnt/TCF-activated population was enriched for colony-forming and invading cells. These actions of PPFP required a functional PPARG DNA binding domain (DBD) within PPFP and were further stimulated by PPARG agonists. These data indicate that PPFP, through its PPARG DBD, induces Wnt/TCF pathway activation in a subpopulation of cells, and these cells have properties of cellular transformation including increased invasiveness and anchorage-independent growth.
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http://dx.doi.org/10.1530/ERC-13-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839064PMC
October 2013

Welcome to the 83rd Annual Meeting of the American Thyroid Association.

Thyroid 2013 Oct;23(10):1185-7

1 Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School , Ann Arbor, Michigan.

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http://dx.doi.org/10.1089/thy.2013.0486DOI Listing
October 2013

Genetics and epigenetics of sporadic thyroid cancer.

Mol Cell Endocrinol 2014 Apr 8;386(1-2):55-66. Epub 2013 Aug 8.

Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Thyroid carcinoma is the most common endocrine malignancy, and although the disease generally has an excellent prognosis, therapeutic options are limited for patients not cured by surgery and radioiodine. Thyroid carcinomas commonly contain one of a small number of recurrent genetic mutations. The identification and study of these mutations has led to a deeper understanding of the pathophysiology of this disease and is providing new approaches to diagnosis and therapy. Papillary thyroid carcinomas usually contain an activating mutation in the RAS cascade, most commonly in BRAF and less commonly in RAS itself or through gene fusions that activate RET. A chromosomal translocation that results in production of a PAX8-PPARG fusion protein is found in follicular carcinomas. Anaplastic carcinomas may contain some of the above changes as well as additional mutations. Therapies that are targeted to these mutations are being used in patient care and clinical trials.
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http://dx.doi.org/10.1016/j.mce.2013.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867574PMC
April 2014

The relationship between extent of thyroid cancer surgery and use of radioactive iodine.

Ann Surg 2013 Aug;258(2):354-8

Divisions of Metabolism, Endocrinology, and Diabetes and Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109, USA.

Unlabelled: By linking surgeon surveys to the National Cancer Database, we found that surgeons' tendency to perform more extensive thyroid resection is associated with greater use of radioactive iodine for stage I thyroid cancer.

Objective: To determine the relationships between surgeon recommendations for extent of resection and radioactive iodine use in low-risk thyroid cancer.

Background: There has been an increase in thyroid cancer treatment intensity; the relationship between extent of resection and medical treatment with radioactive iodine remains unknown.

Methods: We randomly surveyed thyroid surgeons affiliated with 368 hospitals with Commission on Cancer-accredited cancer programs. Survey responses were linked to the National Cancer Database. The relationship between extent of resection and the proportion of the American Joint Committee on Cancer stage I well-differentiated thyroid cancer patients treated with radioactive iodine after total thyroidectomy was assessed with multivariable weighted regression, controlling for hospital and surgeon characteristics.

Results: The survey response rate was 70% (560/804). Surgeons who recommend total thyroidectomy over lobectomy for subcentimeter unifocal thyroid cancer were significantly more likely to recommend prophylactic central lymph node dissection for thyroid cancer regardless of tumor size (P < 0.001). They were also more likely to favor radioactive iodine in patients with intrathyroidal unifocal cancer ≤1 cm (P = 0.001), 1.1-2 cm (P = 0.004), as well as intrathyroidal multifocal cancer ≤1 cm (P = 0.004). In multivariable analysis, high hospital case volume, fewer surgeon years of experience, general surgery specialty, and preference for more extensive resection were independently associated with greater hospital-level use of radioactive iodine for stage I disease.

Conclusions: In addition to surgeon experience and specialty, surgeons' tendency to perform more extensive thyroid resection is associated with greater use of radioactive iodine for stage I thyroid cancer.
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http://dx.doi.org/10.1097/SLA.0b013e31826c8915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708979PMC
August 2013

Variation in the management of thyroid cancer.

J Clin Endocrinol Metab 2013 May 28;98(5):2001-8. Epub 2013 Mar 28.

Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.

Context: Little is known about practice patterns in thyroid cancer, a cancer that is increasing in incidence.

Objective: We sought to identify aspects of thyroid cancer management that have the greatest variation.

Design/setting/participants: We surveyed 944 physicians involved in thyroid cancer care from 251 hospitals affiliated with the US National Cancer Database. Physicians were asked questions in the following four domains: thyroid surgery, radioactive iodine use, thyroid hormone replacement postsurgery, and long-term thyroid cancer management. We calculated the ratio of observed variation to hypothetical maximum variation under the assumed distribution of the response. Ratios closer to 1 indicate greater variation.

Results: We had a 66% response rate. We found variation in multiple aspects of thyroid cancer management, including the role of central lymph node dissections (variation, 0.99; 95% confidence interval [CI], 0.98-1.00), the role of pretreatment scans before radioactive iodine treatment (variation, 1.00; 95% CI, 0.98-1.00), and all aspects of long-term thyroid cancer management, including applications of ultrasound (variation, 0.97; 95% CI, 0.93-0.99) and radioactive iodine scans (variation, 0.99; 95% CI, 0.97-1.00). For the management of small thyroid cancers, variation exists in all domains, including optimal extent of surgery (variation, 0.91; 95% CI, 0.88-0.94) and the role of both radioactive iodine treatment (variation, 0.91; 95% CI, 0.89-0.93) and suppressive doses of thyroid hormone replacement (variation, 1.00; 95% CI, 0.99-1.00).

Conclusion: We identified areas of variation in thyroid cancer management. To reduce the variation and improve the management of thyroid cancer, there is a need for more research and more research dissemination.
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http://dx.doi.org/10.1210/jc.2012-3355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644603PMC
May 2013

Referral patterns for patients with high-risk thyroid cancer.

Endocr Pract 2013 Jul-Aug;19(4):638-43

Department of Medicine, University of Michigan, Ann Arbor, MI 48109-2800, USA.

Objective: Knowledge of referral patterns for specialty cancer care is sparse. Information on both the need and reasons for referral of high-risk, well-differentiated thyroid cancer patients should provide a foundation for eliminating obstacles to appropriate patient referrals and improving patient care.

Methods: We surveyed 370 endocrinologists involved in thyroid cancer management. From information in a clinical vignette, respondents were asked to identify the reasons they would need to refer a high-risk patient to a more specialized facility for care. We performed multivariable analysis controlling for hospital and physician characteristics.

Results: Thirty-two percent of respondents reported never referring thyroid cancer patients to another facility. Of those that would refer a high-risk patient to another facility, the opportunity for a patient to enter a clinical trial was the most common reason reported (44%), followed by high-dose radioactive iodine (RAI) with or without dosimetry (33%), lateral neck dissection (24%), and external beam radiation (15%). In multivariable analysis, endocrinologists with a higher percentage of their practice devoted to thyroid cancer care were significantly less likely to refer patients to another facility (P = .003).

Conclusion: The majority of endocrinologists treating thyroid cancer patients report referring a high-risk patient to another facility for some or all of their care. Knowledge of the patterns of physician referrals and the likelihood of need for referral are key to understanding discrepancies in referral rates and obstacles in the referral process.
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http://dx.doi.org/10.4158/EP12288.ORDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747229PMC
March 2014

Factors that influence radioactive iodine use for thyroid cancer.

Thyroid 2013 Feb;23(2):219-24

Division of Metabolism, Endocrinology, and Diabetes, Department of Medicine, University of Michigan Health System, University of Michigan, Ann Arbor, Michigan, USA.

Background: There is variation in the use of radioactive iodine (RAI) as treatment for well-differentiated thyroid cancer. The factors involved in physician decision-making for RAI remain unknown.

Methods: We surveyed physicians involved in postsurgical management of patients with thyroid cancer from 251 hospitals. Respondents were asked to rate the factors important in influencing whether a thyroid cancer patient receives RAI. Multivariable analyses controlling for physician age, gender, specialty, case volume, and whether they personally administer RAI, were performed to determine correlates of importance placed on patients' and physicians' worry about death from cancer and differences between low- versus higher-case-volume physicians.

Results: The survey response rate was 63% (534/853). Extent of disease, adequacy of surgical resection, patients' willingness to receive RAI, and patients' age were the factors physicians were most likely to report as quite or very important in influencing recommendations for RAI to patients with thyroid cancer. Interestingly, both physicians' and patients' worry about death from thyroid cancer were also important in determining RAI use. Physicians with less thyroid cancer cases per year were more likely than higher-volume physicians to report patients' (p<0.001) and physicians' worry about death (p=0.016) as quite or very important in decision-making. Other factors more likely to be of greater importance in determining RAI use for physicians with lower thyroid cancer patient volume versus higher include the accepted standard at the affiliated hospital (p=0.020), beliefs about RAI expressed by colleagues comanaging patients (p=0.003), and patient distance from the nearest facility administering RAI (p=0.012).

Conclusion: In addition to the extent of disease and adequacy of surgical resection, physicians place importance on physician and patient worry about death from thyroid cancer when deciding whether to treat a patient with RAI. The factors important to physician decision-making differ based on physician thyroid-cancer case-volume, with worry about death being more influential for low-case-volume physicians. As the mortality from thyroid cancer is low, the importance placed on death in decision making may be unwarranted.
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http://dx.doi.org/10.1089/thy.2012.0380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569922PMC
February 2013

The role of clinicians in determining radioactive iodine use for low-risk thyroid cancer.

Cancer 2013 Jan 28;119(2):259-65. Epub 2012 Jun 28.

Division of Metabolism, Endocrinology, and Diabetes, Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.

Background: There is controversy regarding the optimal management of thyroid cancer. The proportion of patients with low-risk thyroid cancer who received radioactive iodine (RAI) treatment increased over the last 20 years, and little is known about the role played by clinicians in hospital-level RAI use for low-risk disease.

Methods: Thyroid surgeons affiliated with 368 hospitals that had Commission on Cancer-accredited cancer programs were surveyed. Survey data were linked to data reported to the National Cancer Database. A multivariable analysis was used to assess the relation between clinician decision makers and hospital-level RAI use after total thyroidectomy in patients with stage I, well differentiated thyroid cancer.

Results: The survey response rate was 70% (560 of 804 surgeons). The surgeon was identified as the primary decision maker by 16% of the surgeons; the endocrinologist was identified as the primary decision maker by 69%, and a nuclear medicine, radiologist, or other physician was identified as the primary decision maker by 15%. In a multivariable analysis controlling for hospital case volume and hospital type, when the primary decision maker was in a specialty other than endocrinology or surgery, there was greater use of RAI at the hospital (P < .001). A greater number of providers at the hospital where RAI was administered and having access to a tumor board also were associated with increased use of RAI (P < .001 and P = .006, respectively).

Conclusions: The specialty of the primary decision maker, the number of providers administering RAI, and having access to a tumor board were associated significantly with the use of RAI for stage I thyroid cancer. The findings have implications for addressing nonclinical variation between hospitals, with a marked heterogeneity in decision making suggesting that standardization of care will be challenging.
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http://dx.doi.org/10.1002/cncr.27721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465617PMC
January 2013

Pioglitazone induces a proadipogenic antitumor response in mice with PAX8-PPARgamma fusion protein thyroid carcinoma.

Endocrinology 2011 Nov 27;152(11):4455-65. Epub 2011 Sep 27.

Division of Metabolism, Endocrinology and Diabetes, Unit for Laboratory Animal Medicine, Department of Pathology, University of Michigan Medical School, 1150 West Medical Center Drive, 5560 MSRB2, Ann Arbor, Michigan 48109, USA.

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.
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http://dx.doi.org/10.1210/en.2011-1178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199014PMC
November 2011

Use of radioactive iodine for thyroid cancer.

JAMA 2011 Aug;306(7):721-8

Division of Metabolism, Endocrinology, and Diabetes, Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Context: Substantial uncertainty persists about the indications for radioactive iodine for thyroid cancer. Use of radioactive iodine over time and the correlates of its use remain unknown.

Objective: To determine practice patterns, the degree to which hospitals vary in their use of radioactive iodine, and factors that contribute to this variation.

Design, Setting, And Patients: Time trend analysis of radioactive iodine use in a cohort of 189,219 patients with well-differentiated thyroid cancer treated at 981 hospitals associated with the US National Cancer Database between 1990 and 2008. We used multilevel analysis to assess the correlates of patient and hospital characteristics on radioactive iodine use in the cohort treated from 2004 to 2008.

Main Outcome Measure: Use of radioactive iodine after total thyroidectomy.

Results: Between 1990 and 2008, across all tumor sizes, there was a significant increase in the proportion of patients with well-differentiated thyroid cancer receiving radioactive iodine (1373/3397 [40.4%] vs 11,539/20,620 [56.0%]; P < .001). Multivariable analysis of patients treated from 2004 to 2008 found that there was a statistical difference in radioactive iodine use between American Joint Committee on Cancer stages I and IV (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.31-0.37) but not between stages II/III and IV (for stage II vs stage IV, OR, 0.97; 95% CI, 0.88-1.07 and for stage III vs stage IV, OR, 1.06; 95% CI, 0.95-1.17). In addition to patient and tumor characteristics, hospital volume was associated with radioactive iodine use. Wide variation in radioactive iodine use existed, and only 21.1% of this variation was accounted for by patient and tumor characteristics. Hospital type and case volume accounted for 17.1% of the variation. After adjusting for available patient, tumor, and hospital characteristics, 29.1% of the variance was attributable to unexplained hospital characteristics.

Conclusion: Among patients treated for well-differentiated thyroid cancer at hospitals in the National Cancer Database, there was an increase in the proportion receiving radioactive iodine between 1990 and 2008; much of the variation in use was associated with hospital characteristics.
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http://dx.doi.org/10.1001/jama.2011.1139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352591PMC
August 2011

Multiple roles for the non-coding RNA SRA in regulation of adipogenesis and insulin sensitivity.

PLoS One 2010 Dec 2;5(12):e14199. Epub 2010 Dec 2.

Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.

Peroxisome proliferator-activated receptor-γ (PPARγ) is a master transcriptional regulator of adipogenesis. Hence, the identification of PPARγ coactivators should help reveal mechanisms controlling gene expression in adipose tissue development and physiology. We show that the non-coding RNA, Steroid receptor RNA Activator (SRA), associates with PPARγ and coactivates PPARγ-dependent reporter gene expression. Overexpression of SRA in ST2 mesenchymal precursor cells promotes their differentiation into adipocytes. Conversely, knockdown of endogenous SRA inhibits 3T3-L1 preadipocyte differentiation. Microarray analysis reveals hundreds of SRA-responsive genes in adipocytes, including genes involved in the cell cycle, and insulin and TNFα signaling pathways. Some functions of SRA may involve mechanisms other than coactivation of PPARγ. SRA in adipocytes increases both glucose uptake and phosphorylation of Akt and FOXO1 in response to insulin. SRA promotes S-phase entry during mitotic clonal expansion, decreases expression of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1, and increases phosphorylation of Cdk1/Cdc2. SRA also inhibits the expression of adipocyte-related inflammatory genes and TNFα-induced phosphorylation of c-Jun NH(2)-terminal kinase. In conclusion, SRA enhances adipogenesis and adipocyte function through multiple pathways.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014199PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996286PMC
December 2010

Dax1 up-regulates Oct4 expression in mouse embryonic stem cells via LRH-1 and SRA.

Mol Endocrinol 2010 Dec 13;24(12):2281-91. Epub 2010 Oct 13.

Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.

Dax1 (Nr0b1) is an atypical orphan nuclear receptor that has recently been shown to play a role in mouse embryonic stem (mES) cell pluripotency. Here we describe a mechanism by which Dax1 maintains pluripotency. In steroidogenic cells, Dax1 protein interacts with the NR5A nuclear receptor steroidogenic factor 1 (Nr5a1) to inhibit transcription of target genes. In mES cells, liver receptor homolog 1 (LRH-1, Nr5a2), the other NR5A family member, is expressed, and LRH-1 has been shown to interact with Dax1. We demonstrate by coimmunoprecipitation that Dax1 is, indeed, able to form a complex with LRH-1 in mES cells. Because Dax1 was historically characterized as an inhibitor of steroidogenic factor 1-mediated transcriptional activation, we hypothesized that Dax1 would inhibit LRH-1 action in mES cells. Therefore, we examined the effect of Dax1 on the LRH-1-mediated activation of the critical ES cell factor Oct4 (Pou5f1). Chromatin immunoprecipitation localized Dax1 to the Oct4 promoter at the LRH-1 binding site, and luciferase assays together with Dax1 overexpression and knockdown experiments revealed that, rather than repress, Dax1 accentuated LRH-1-mediated activation of the Oct4 gene. Similar to our previously published studies that defined the RNA coactivator steroid receptor RNA activator as the critical mediator of Dax1 coactivation function, Dax1 augmentation of LRH-1-mediated Oct4 activation is dependent upon steroid receptor RNA activator. Finally, utilizing published chromatin immunoprecipitation data of whole-genome binding sites of LRH-1 and Dax1, we show that LRH-1 and Dax1 commonly colocalize at 288 genes (43% of LRH-1 target genes), many of which are involved in mES cell pluripotency. Thus, our results indicate that Dax1 plays an important role in the maintenance of pluripotency in mES cells through interaction with LRH-1 and transcriptional activation of Oct4 and other genes.
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http://dx.doi.org/10.1210/me.2010-0133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999479PMC
December 2010

A phase II study of imatinib in patients with advanced anaplastic thyroid cancer.

Thyroid 2010 Sep;20(9):975-80

Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

Background: Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib.

Methods: Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual.

Results: From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths.

Conclusions: Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting.
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http://dx.doi.org/10.1089/thy.2010.0057DOI Listing
September 2010

Detection of the PAX8-PPARgamma fusion protein in thyroid tumors.

Authors:
Ronald J Koenig

Clin Chem 2010 Mar 14;56(3):331-3. Epub 2010 Jan 14.

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http://dx.doi.org/10.1373/clinchem.2009.137679DOI Listing
March 2010

Paired box gene 8-peroxisome proliferator-activated receptor-gamma fusion protein and loss of phosphatase and tensin homolog synergistically cause thyroid hyperplasia in transgenic mice.

Endocrinology 2009 Nov 24;150(11):5181-90. Epub 2009 Sep 24.

University of Michigan, 5560 MSRB-2, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-5678, USA.

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.
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http://dx.doi.org/10.1210/en.2009-0701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775974PMC
November 2009