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THYROID HORMONE RECEPTOR BETA INDUCES A TUMOR SUPPRESSIVE PROGRAM IN ANAPLASTIC THYROID CANCER.

甲状腺激素受体 β 诱导未分化甲状腺癌的肿瘤抑制程序。

  • 影响因子:4.67
  • DOI:10.1158/1541-7786.MCR-20-0282
  • 作者列表:"Bolf EL","Gillis NE","Davidson CD","Rodriguez PD","Cozzens L","Tomczak JA","Frietze S","Carr FE
  • 发表时间:2020-06-17
Abstract

:The thyroid hormone receptor beta (TRβ), a key regulator of cellular growth and differentiation, is frequently dysregulated in cancers. Diminished expression of TRβ is noted in thyroid, breast, and other solid tumors and is correlated with more aggressive disease. Restoration of TRβ levels decreased tumor growth supporting the concept that TRβ could function as a tumor suppressor. Yet, the TRβ tumor suppression transcriptome is not well delineated and the impact of TRβ is unknown in aggressive anaplastic thyroid cancer (ATC). Here, we establish that restoration of TRβ expression in the human ATC cell line SW1736 (SW-TRβ) reduces the aggressive phenotype, decreases cancer stem-cell populations and induces cell death in a T3-dependent manner. Transcriptomic analysis of SW-TRβ cells via RNA-sequencing revealed distinctive expression patterns induced by ligand-bound TRβ and revealed novel molecular signaling pathways. Of note, liganded TRβ repressed multiple nodes in the PI3K/AKT pathway, induced expression of thyroid differentiation markers, and promoted pro-apoptotic pathways. Our results further revealed the JAK1-STAT1 pathway as a novel, T3-mediated, anti-tumorigenic pathway that can be activated in additional ATC lines. These findings elucidate a TRβ-driven tumor suppression transcriptomic signature, highlight unexplored therapeutic options for ATC, and support TRβ activation as a promising therapeutic option in cancers. Implications: TRβ-T3 induced a less aggressive phenotype and tumor suppression program in anaplastic thyroid cancer cells revealing new potential therapeutic targets.

摘要

: 甲状腺激素受体 β (tr β) 是细胞生长和分化的关键调节因子,在癌症中经常失调。在甲状腺、乳腺和其他实体瘤中观察到 tr β 表达减少,并与更具侵袭性的疾病相关。Tr β 水平的恢复降低了肿瘤生长,支持 tr β 可以作为肿瘤抑制因子发挥作用的概念。然而,tr β 肿瘤抑制转录组没有很好地描述,tr β 在侵袭性未分化甲状腺癌 (ATC) 中的影响尚不清楚。在这里,我们建立了人 ATC 细胞系 SW1736 (SW-tr β) 中 tr β 表达的恢复降低了侵袭性表型,减少癌症干细胞群并以 T3-dependent 的方式诱导细胞死亡。通过 RNA 测序对 SW-tr β 细胞进行转录组学分析,揭示了配体结合的 tr β 诱导的独特表达模式,揭示了新的分子信号通路。值得注意的是,liganded tr β 抑制了 PI3K/AKT 通路中的多个节点,诱导了甲状腺分化标志物的表达,并促进了促凋亡通路。我们的研究结果进一步揭示了 JAK1-STAT1 通路是一种新的、 T3-mediated 的、可在额外的 ATC 线路中激活的抗肿瘤通路。这些发现阐明了 tr β 驱动的肿瘤抑制转录组学特征,突出了 ATC 的未开发治疗选择,并支持 tr β 活化作为癌症有希望的治疗选择。意义: tr β-t3 在未分化甲状腺癌细胞中诱导了较不侵袭性的表型和肿瘤抑制程序,揭示了新的潜在治疗靶点。

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影响因子:2.13
发表时间:2020-01-02
DOI:10.1093/ajcp/aqz145
作者列表:["Travaglino A","Pace M","Varricchio S","Insabato L","Giordano C","Picardi M","Pane F","Staibano S","Mascolo M"]

METHODS:OBJECTIVES:To assess the prevalence of Hashimoto thyroiditis (HT) in primary thyroid lymphoma (PTL) and whether it differs between mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL). METHODS:Electronic databases were searched for studies assessing HT prevalence in PTL, based on antithyroid antibodies, clinical history, or pathology. Pooled prevalence of HT and its association with histotype (MALT or DLBCL) were calculated. RESULTS:Thirty-eight studies with 1,346 PTLs were included. Pooled prevalence results were 78.9% (any HT evidence), 65.3% (antithyroid antibodies), 41.7% (clinical history), and 64% (pathology). HT prevalence was significantly higher in MALT lymphoma than in DLBCL (P = .007) and in mixed DLBCL/MALT than in pure DLBCL (P = .002). CONCLUSIONS:Overall, 78.9% of patients with PTL have any HT evidence, but only half of these had been clinically followed. The difference in HT prevalence suggests that a subset of DLBCL may not derive from MALT lymphoma.

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影响因子:2.24
发表时间:2020-01-08
DOI:10.1007/s00268-019-05337-9
作者列表:["Lee, Inhwa","Kim, Hyeung Kyoo","Soh, Euy Young","Lee, Jeonghun"]

METHODS:Background Whether chronic lymphocytic thyroiditis (CLT) influences the risk of development and the progression of papillary thyroid cancer (PTC) remains uncertain. We investigated the effects of CLT on the clinicopathologic features and prognosis of PTC. Methods Two thousand nine hundred twenty-eight consecutive patients with PTC treated between 2009 and 2017 were divided into two groups: one with chronic lymphocytic thyroiditis and one without; 1174 (40%) of the patients had coincident CLT. Results In univariate analysis, CLT correlated positively with small tumor size, frequent extrathyroidal extension, multifocal diseases, and p53 but negatively with central lymph node (LN) metastasis and BRAF mutation. In multivariate analysis, CLT was associated with extrathyroidal extension and multifocal disease; however, it was not a prognostic factor for recurrence even though it was associated with two aggressive factors. Compared with patients with PTC alone, there were more retrieved central LNs in the PTC + CLT group, and these patients also underwent more invasive diagnostic tests such as fine needle aspiration cytology and frozen biopsy of LN. Conclusions The CLT patients with PTC had better behavior features and prognoses than did those with PTC alone despite frequent multifocality and extrathyroidal extension. However, precaution may be necessary to avoid performing invasive diagnostic procedures for lateral LN metastasis and to manage the patients appropriately.

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影响因子:2.69
发表时间:2020-01-29
DOI:10.1016/j.bbrc.2019.11.047
作者列表:["Zhang Z","Xu T","Qin W","Huang B","Chen W","Li S","Li J"]

METHODS::PTPN2 is one of the members of the protein Tyrosine Phosphatases (PTPs) family. To explore the promotive effect of upregulated PTPN2 induced by inflammatory response or oxidative stress on the progression of thyroid cancer. PTPN2 level in thyroid cancer tissues and cell lines was detected. Kaplan-Meier method was applied for evaluating the prognostic value of PTPN2 in thyroid cancer patients. After stimulation of inflammatory response (treatment of IFN-γ and TNF-α), or oxidative stress (treatment of H2O2), protein level of PTPN2 in K1 cells was measured by Western blot. Regulatory effects of PTPN2 on EdU-positive staining and Ki-67 positive cell ratio in K1 cells either with H2O2 stimulation or not were determined. PTPN2 was upregulated in thyroid cancer tissues and cell lines. Its level was higher in metastatic thyroid cancer patients than those of non-metastatic ones. High level of PTPN2 predicted worse prognosis of thyroid cancer. Treatment of either IFN-γ or TNF-α upregulated protein level of PTPN2 in K1 cells. Meanwhile, H2O2 stimulation upregulated PTPN2, which was reversed by NAC administration. With the stimulation of increased doses of H2O2, EdU-positive staining and Ki-67 positive cell ratio were dose-dependently elevated. Silence of PTPN2 attenuated proliferative ability and Ki-67 expression in K1 cells either with H2O2 stimulation or not. Inflammatory response or oxidative stress induces upregulation of PTPN2, thus promoting the progression of thyroid cancer.

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