Orphan Nuclear Receptor TR3 in tumor angiogenesis and associated microvessel perm

孤儿核受体 TR3 在肿瘤血管生成和相关微血管生成中的作用

• 批准号: 8465198
• 负责人: HUIYAN ZENG
• 金额: $ 32.16万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-07 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465198
• 关键词: Adherence; Adherens Junction; Adult; Adverse effects; Angiogenic Factor; Antibodies; Area; Avastin; Binding Sites; Cell Proliferation; Cell Survival; Cells; Colon; Colon Carcinoma; Complementary DNA; Complex; Data; Defect; Development; Dominant-Negative Mutation; Down-Regulation; ETS1 gene; Edema; Effectiveness; Endothelial Cells; Endothelium; Family member; Gases; Goals; Grant; Growth; Human; In Vitro; Intercellular Junctions; Knockout Mice; Length; Lewis Lung Carcinoma; Matrix Metalloproteinases; Mediating; Messenger RNA; Molecular; Mus; NR4A1 gene; Nucleic Acid Regulatory Sequences; Pathologic Neovascularization; Permeability; Plasma Proteins; Play; Proliferating; Protein Family; Proteins; Refuse Disposal; Regulation; Reporting; Role; Signal Transduction; Solid Neoplasm; Staging; Testing; Tetracyclines; Therapeutic; Tissues; Toxic effect; Transactivation; Transcription Coactivator; Transgenes; Transgenic Mice; Tumor Angiogenesis; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascular blood supply; Wild Type Mouse; Work; adherent junction; analog; angiogenesis; cadherin 5; cancer therapy; cancer type; density; humanized antibody; in vivo; insight; matrigel; melanoma; nutrition; orphan nuclear receptor TR3; overexpression; promoter; therapeutic target; transcription factor; transgene expression; tumor; tumor growth; tumorigenesis

Summary In order to grow beyond minimal size (3 mm3), tumors must generate a new vascular supply (angiogenesis) for the purpose of gas exchange, cell nutrition, and waste disposal. Among many angiogenic factors, VEGF-A has been shown to be the most important one in tumor angiogenesis and associated microvessel permeability to plasma proteins. A humanized antibody to VEGF-A165, Avastin, has been developed and shown to be effective in treating several types of cancers. However, Avastin has significant toxic side effects. Therefore, it is desirable to identify whether downstream targets of VEGF signaling can be used as promising therapeutic targets with less toxic effects. Our recent work showed that the orphan nuclear receptor TR3 (mouse analogue, Nur77) was highly upregulated by VEGF-A165 in cultured endothelial cells and in pathological angiogenesis and that it was required for VEGF-A165-induced endothelial cell proliferation and survival in vitro and Matrigel angiogenesis in vivo. Overexpression of TR3 cDNA induced endothelial cell proliferation and survival in vitro and in Matrigel angiogenesis in vivo, even in the absence of VEGF-A165. The transcriptional activity of TR3 is required for its function in angiogenesis. Further, B16 melanoma growth was completely inhibited in Nur77-/- mice, most likely through inhibition of tumor angiogenesis. Nur77-/- mice have no obvious developmental defect. Our overall hypothesis is that TR3/Nur77 regulates tumor growth through regulation of angiogenesis and associated microvessel permeability. To prove our hypothesis and gain insight into the molecular mechanisms, we will study tumor growth in transgenic mice that Nur77 activity is inhibited in mouse endothelium in Aim 1. Our second aim will investigate that TR3/Nur77 regulates tumor angiogenesis and its associated microvessel permeability by destabilization of VE-cadherin adherences junctions. In the last aim, we will delineate the transcriptional mechanisms by which TR3 regulates VE-cadherin expression. The information from this study will not only enhance our understanding of the pathophyiosiology of tumorigenesis but also help us to develop effective therapeutic approaches for treatment of cancers.

摘要 为了超过最小尺寸(3mm3)，肿瘤必须产生新的血管供应(血管生成)。 用于气体交换、细胞营养和废物处理。在众多血管生成因子中，血管内皮生长因子-A 已被证明是肿瘤血管生成和相关的微血管通透性中最重要的一个 到血浆蛋白。一种人源化的抗血管内皮生长因子-A165的抗体阿瓦斯丁已经被开发出来并被证明是 在治疗几种癌症方面有效。然而，阿瓦斯丁有显著的毒副作用。因此，它 确定血管内皮生长因子信号的下游靶点是否可以作为有前景的治疗手段是可取的 毒性较小的目标。我们最近的工作表明，孤儿核受体TR3(小鼠 类似物，Nur77)在培养的内皮细胞中被血管内皮细胞生长因子A165高度上调 血管生成在血管内皮生长因子-A165诱导的血管内皮细胞增殖和存活中的作用 体内Matrigel血管生成。TR3基因过表达诱导内皮细胞增殖 体外存活和体内Matrigel血管生成，即使在没有血管内皮生长因子-A165的情况下也是如此。转录本 TR3的活性是其血管生成功能所必需的。此外，B16黑色素瘤的生长完全是 在Nur77-/-小鼠中被抑制，很可能是通过抑制肿瘤血管生成。Nur77-/-小鼠没有明显的 发育缺陷。我们的总体假设是，TR3/Nur77通过调节 血管生成和相关的微血管通透性。为了证明我们的假设并深入了解 分子机制，我们将在转基因小鼠中研究Nur77活性被抑制的转基因小鼠的肿瘤生长 目的1.我们的第二个目的是研究TR3/Nur77调控肿瘤血管生成及其机制。 VE-钙粘附素黏附连接失稳导致的相关微血管通透性。在最后一个目标中， 我们将描述TR3调节VE-钙粘蛋白表达的转录机制。这个 来自这项研究的信息不仅将增强我们对肿瘤发生的病理生理学的理解 而且还有助于我们开发有效的治疗癌症的方法。

项目成果

Expressions of Orphan Nuclear Receptor TR3/Nur77 in Chronic Hepatopathy and Its Clinical Significance.

• DOI: 10.4172/2324-9110.1000188
• 发表时间: 2017-06
• 期刊: Journal of clinical & experimental oncology
• 作者: Yingling Zeng;X. Ye;D. Liao;Shizhang Huang;Huinan Mao;Dezheng Zhao;H. Zeng

Down Syndrome Candidate Region 1 Isoform 1L regulated tumor growth by targeting both angiogenesis and tumor cells.

• DOI: 10.1016/j.mvr.2021.104305
• 发表时间: 2022-03
• 期刊: MICROVASCULAR RESEARCH
• 影响因子: 3.1
• 作者: Chen, Chen;Cui, Pengfei;Zhao, Kevin;Niu, Gengming;Hou, Shiqiang;Zhao, Dezheng;Zeng, Huiyan
• 通讯作者: Zeng, Huiyan

Orphan Nuclear Receptor TR3/Nur77 is a Specific Therapeutic Target for Hepatic Cancers.

• DOI: 10.4172/2324-9110.1000184
• 发表时间: 2017-05
• 期刊: Journal of clinical & experimental oncology
• 作者: Yingling Zeng;X. Ye;D. Liao;Shizhang Huang;Huinan Mao;Dezheng Zhao;H. Zeng

A novel transcriptional complex on the VE-cadherin promoter regulated the downregulation of VE-cadherin in the Down Syndrome Candidate Region 1 isoform 1L-mediated angiogenesis.

• DOI: 10.1016/j.mvr.2021.104209
• 发表时间: 2021-11
• 期刊: MICROVASCULAR RESEARCH
• 影响因子: 3.1
• 作者: Hou, Shiqiang;Niu, Gengming;Liu, Xin;Bourbon, Pierre M.;Zhang, Dongmei;Cui, Pengfei;Zhao, Kevin;Zhao, Dezheng;Zeng, Huiyan
• 通讯作者: Zeng, Huiyan