Publications by authors named "Jingcheng Yu"

12 Publications

  • Page 1 of 1

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

SOX11 promotes osteoarthritis through induction of TNF-α.

Pathol Res Pract 2019 Jul 6;215(7):152442. Epub 2019 May 6.

Department of orthopedics, Zhangjiagang Hospital of Traditional Chinese Medicine, Zhangjiagang, Jiangsu 215600, China.

Objective: Osteoarthritis (OA) is a degenerative disease and the molecular mechanism of OA remains unclear. Transcription factor SOX11 has been proved to be involved in the development progress of OA. The present study aimed to evaluate the potential function of SOX11 during the development of OA.

Methods: SOX11 expression in patients with OA and health donator was determined with qRT-PCR. Subsequently, in vitro OA model was established by treating the chondrocyte cells CHON-001 with IL-1β. Next, we validated the function of SOX11 in in vitro OA model by using siRNAs. Finally, the relationship between SOX11 and TNF-α was explored.

Results: SOX11 was upregulated in patients with OA and in IL-1β treated cells. IL-1β significantly increased both the mRNA and protein levels of MMP13 and cleaved caspase 3, while decreased collagen II and aggrecan in CHON-001 cells. In addition, knockdown of SOX11 could significantly decrease IL-1β-induced apoptosis in CHON-001 cells. Meanwhile, IL-1β induced OA like phenomenon was significantly reversed by siRNA interference. Moreover, inhibition of SOX11 decreased the level of TNF-α in patients with OA and in IL-1β treated cell supernatant.

Conclusion: Inhibition of SOX11 could improve IL-1β-induced OA like phenomenon in CHON-001 cells, which suggesting SOX11 played an important role during the pathogenesis of OA. Thus, we hypothesized that SOX11 could be a potential target for the treatment of patients with OA.
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http://dx.doi.org/10.1016/j.prp.2019.152442DOI Listing
July 2019

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

Application of esophageal radiography technique in the treatment of herniation of cervical disc with radiofrequency thermocoagulation and target ablation.

J Neurosurg Sci 2019 Oct 4;63(5):615-617. Epub 2017 Sep 4.

Department of Traumatic Orthopedics, Zhangjiagang Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China -

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http://dx.doi.org/10.23736/S0390-5616.17.04165-0DOI Listing
October 2019

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

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

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

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

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

Podocyte specific knock out of selenoproteins does not enhance nephropathy in streptozotocin diabetic C57BL/6 mice.

BMC Nephrol 2008 Jul 22;9. Epub 2008 Jul 22.

Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109-5678, USA.

Background: Selenoproteins contain selenocysteine (Sec), commonly considered the 21st genetically encoded amino acid. Many selenoproteins, such as the glutathione peroxidases and thioredoxin reductases, protect cells against oxidative stress by functioning as antioxidants and/or through their roles in the maintenance of intracellular redox balance. Since oxidative stress has been implicated in the pathogenesis of diabetic nephropathy, we hypothesized that selenoproteins protect against this complication of diabetes.

Methods: C57BL/6 mice that have a podocyte-specific inability to incorporate Sec into proteins (denoted in this paper as PodoTrsp-/-) and control mice were made diabetic by intraperitoneal injection of streptozotocin, or were injected with vehicle. Blood glucose, body weight, microalbuminuria, glomerular mesangial matrix expansion, and immunohistochemical markers of oxidative stress were assessed.

Results: After 3 and 6 months of diabetes, control and PodoTrsp-/- mice had similar levels of blood glucose. There were no differences in urinary albumin/creatinine ratios. Periodic acid-Schiff staining to examine mesangial matrix expansion also demonstrated no difference between control and PodoTrsp-/- mice after 6 months of diabetes, and there were no differences in immunohistochemical stainings for nitrotyrosine or NAD(P)H dehydrogenase, quinone 1.

Conclusion: Loss of podocyte selenoproteins in streptozotocin diabetic C57BL/6 mice does not lead to increased oxidative stress as assessed by nitrotyrosine and NAD(P)H dehydrogenase, quinone 1 immunostaining, nor does it lead to worsening nephropathy.
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http://dx.doi.org/10.1186/1471-2369-9-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2494546PMC
July 2008

Induction of type 1 iodothyronine deiodinase to prevent the nonthyroidal illness syndrome in mice.

Endocrinology 2006 Jul 6;147(7):3580-5. Epub 2006 Apr 6.

Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, 48109-0678, USA.

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.
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http://dx.doi.org/10.1210/en.2005-1443DOI Listing
July 2006