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首页> 外文学位 >The role of NRF2 on VEGFA/VEGFR expression, hepatic vascularization and cancer growth.
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The role of NRF2 on VEGFA/VEGFR expression, hepatic vascularization and cancer growth.

机译：NRF2对VEGFA / VEGFR表达，肝血管生成和癌症生长的作用。

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摘要

The transcriptional enhancer protein Nuclear factor (erythroid-derived 2)-like 2 (NRF2) stimulates expression of a wide range of genes in response to oxidative and electrophilic stress via binding to the DNA element known as the antioxidant response element (ARE) to maintain organismal homeostasis. While previous research initially identified the importance of NRF2 in drug detoxication, further research has revealed transactivation of genes that function more broadly, including those that influence energy metabolism and tissue regeneration. The goals of this project were to characterize how NRF2 signaling influences the liver microenvironment to affect cancer progression as well as shape the development of the liver vasculature by utilizing genetic mouse models elevated and deficient in NRF2 signaling. Experiments have revealed NRF2 affects transactivation of vascular endothelial growth factor A (VEGFA) directly, through a putative antioxidant response element (ARE) located in the promoter region. To determine how NRF2 could influence the liver microenvironment through alterations VEGFA signaling between hepatocytes and liver sinusoidal endothelial cells, VEGFA and VEGFA receptors were examined in primary isolated cultures. Our studies identified elevated protein levels of VEGFA and reduced protein levels of vascular endothelial growth factor receptor 2 (VEGFR-2) in hepatocytes and liver sinusoidal endothelial cells with both elevated and deficient NRF2 signaling, respectively. Further investigation revealed that increased transcription of hepatocyte growth factor (HGF) was found to coincide with the reduction of VEGFR-2 seen with elevated and deficient NRF2 signaling and that elevated NRF2 signaling also reduced the level of circulating VEGFR-2 protein. The NRF2-dependent alterations to the liver microenvironment were found to enhance cancer progression in mice with elevated and deficient NRF2 signaling. To research if alterations of liver vasculature development were present in NRF2-deficient mice, the hepatic portal vasculature was probed with resin casting. Vascular corrosion casting and Micro-computed tomography (mu-CT) revealed that ductus venosus closure was abolished in many mice. In total, imbalanced NRF2 signaling can enhance cancer progression and alter normal liver development.
机译：转录增强子蛋白核因子（类胡萝卜素衍生的2）样2（NRF2）通过与被称为抗氧化剂响应元件（ARE）的DNA元素结合来刺激多种基因的表达，从而响应氧化应激和亲电子应激有机体内平衡。虽然先前的研究最初确定了NRF2在药物解毒中的重要性，但进一步的研究表明，功能更广泛的基因（包括那些影响能量代谢和组织再生的基因）的反式激活。该项目的目标是通过利用NRF2信号升高和不足的遗传小鼠模型来表征NRF2信号如何影响肝脏微环境以影响癌症进展以及塑造肝脉管系统的发育。实验表明，NRF2通过位于启动子区域的假定抗氧化剂反应元件（ARE）直接影响血管内皮生长因子A（VEGFA）的反式激活。为了确定NRF2如何通过改变肝细胞和肝窦内皮细胞之间的VEGFA信号传导来影响肝脏微环境，在原始分离培养物中检查了VEGFA和VEGFA受体。我们的研究发现，在肝细胞和肝窦窦内皮细胞中，NRF2信号均升高和缺失，VEGFA的蛋白水平升高，而血管内皮生长因子受体2（VEGFR-2）的蛋白水平降低。进一步的研究表明，发现肝细胞生长因子（HGF）的转录增加与NRF2信号升高和不足时所见的VEGFR-2降低相吻合，而NRF2信号升高也降低了循环中VEGFR-2蛋白的水平。发现对肝脏微环境的依赖NRF2的改变可增强具有升高和不足的NRF2信号传导的小鼠的癌症进展。为了研究在NRF2缺陷型小鼠中是否存在肝脏血管系统发育的改变，用树脂浇铸法探测了肝门血管系统。血管腐蚀铸模和微型计算机断层扫描（mu-CT）显示，许多小鼠的静脉导管关闭被取消。总的来说，失衡的NRF2信号传导可以促进癌症进展并改变正常的肝脏发育。

著录项

  • 作者

    Skoko, John J., III.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 265 p.
  • 总页数 265
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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