Plk3 in lung cancer

Plk3 在肺癌中的作用

• 批准号: 8090728
• 负责人: DAZHONG XU
• 金额: $ 8万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090728
• 关键词: Affect; Americas; Angiogenic Factor; Biochemical; Biological; Biology; Cancer Etiology; Cell Proliferation; Cell Survival; Cell model; Cessation of life; Cytokine-Inducible Kinase; Data; Ectopic Expression; Elderly; Elements; Embryo; Environmental Pollutants; Environmental Risk Factor; Environmental and Occupational Exposure; Evaluation; Face; Fibroblast Growth Factor 2; Fibroblasts; Foundations; Gene Expression; Genetic Transcription; HIF1A gene; Hypoxia; Indium; Ions; Knockout Mice; Link; Lung; Malignant neoplasm of lung; Mediating; Metals; Mitogens; Molecular; Mus; Nickel; Nuclear; Occupational Exposure; Phosphorylation; Phosphotransferases; Play; Polo-Box Domain; Process; Procollagen-Proline Dioxygenase; Production; Proteins; Publishing; Regulation; Regulatory Element; Reporting; Residual state; Role; Serine; Smoking; Stress; Study Section; Testing; Tissues; Translations; Tumor Angiogenesis; Tumor Biology; Tumor Suppressor Proteins; Vascular Endothelial Growth Factors; angiogenesis; base; cancer cell; cancer therapy; cancer type; carcinogenesis; cell type; design; hypoxia inducible factor 1; insight; multicatalytic endopeptidase complex; mutant; neoplastic cell; novel; prevent; protein expression; response; therapeutic target; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Lung cancer formation and progression are heavily influenced by environmental factors such as smoking and environmental/occupational exposure. Metal elements such as nickel promote lung cancers. Nickel ion mimics cellular hypoxic responses by elevating the cellular level of hypoxia-inducible factor 1 alpha (HIF-1a) through inhibition of prolyl hydroxylase thereby preventing HIF-1 degradation by proteosomes. Cellular hypoxic responses facilitate tumor progression by regulating gene expression that promotes angiogenesis and cellular adaptation to hypoxia. These processes have increasingly been regarded as prime therapeutic targets for cancer treatments. It is therefore important to understand the basic mechanism of the hypoxic response and angiogenesis in tumor cells, and to identify novel regulatory elements that can serve as therapeutic targets for cancer treatments. Recent studies have revealed a close ties among Polo-like kinase 3 (Plk3), HIF-1a, tumorigenesis, and tumor angiogenesis: Plk3 knockout mice developed highly vascularized tumors in multiple tissues, including the lung, at an advanced age. Plk3-/- mouse embryonic fibroblasts (MEFs) express higher levels of angiogenic factor VEGF. In addition, Plk3 null MEFs express elevated levels of HIF-1a under hypoxic conditions. Furthermore, our most recent studies unveiled a direct regulation of HIF1a by Plk3 through phosphorylation. Plk3 is thus a potential tumor suppressor that regulates cellular hypoxic and angiogenic responses. Based on these previous observations, we hypothesized that Plk3 has a significant role in tumor angiogenesis and nickel-induced carcinogenesis in the lung by inhibiting hypoxic and angiogenic responses of the lung cancer cells. We propose three Specific Aims to test our hypothesis: Aim 1. Studying whether the Plk3 protein level and/or activity is regulated in lung cancer cells under hypoxia and nickel treatments. Aim 2. Determining the role of Plk3 in production of pro-angiogenic factors by lung cancer cells under hypoxia and nickel treatments. Aim 3. Investigating the role of Plk3 in lung cancer cell proliferation and survival under hypoxia and nickel treatments. These Aims are designed to answer two basic questions: 1. Is Plk3 relevant to lung cancer progression? 2. How does Plk3 regulate lung cancer progression? The proposed study should serve as a foundation for further in-depth evaluation on the function of Plk3 in tumor biology and the potential of Plk3 as a therapeutic target for lung cancers. The study should also contribute to our understanding of the mechanisms underlying the environmental relevant metals such as nickel in lung cancers. PUBLIC HEALTH RELEVANCE: The proposed study intends to explore the role of Polo-like kinase 3 (Plk3) in lung cancer. Lung cancer is one of the most prevalent cancer types and the leading cause of cancer-related death in America. It is also one of the most environmentally susceptible cancer types. The proposed study will use biochemical and molecular/cellular biological approaches to investigate the function of Plk3 in lung cancer cell models. The result of this study should provide significant new insights into the biology of lung cancer, the mechanism of how environmental relevant nickel metal affects lung cancer, and the potential of Plk3 as therapeutic target.

描述（由申请人提供）：肺癌的形成和进展很大程度上受到环境因素的影响，例如吸烟和环境/职业暴露。镍等金属元素会促进肺癌。镍离子通过抑制脯氨酰羟化酶来提高缺氧诱导因子 1 α (HIF-1a) 的细胞水平，从而防止 HIF-1 被蛋白酶体降解，从而模拟细胞缺氧反应。细胞缺氧反应通过调节促进血管生成和细胞对缺氧的适应的基因表达来促进肿瘤进展。这些过程越来越被视为癌症治疗的主要治疗靶点。因此，了解肿瘤细胞缺氧反应和血管生成的基本机制，并确定可作为癌症治疗靶点的新型调控元件非常重要。最近的研究揭示了 Polo 样激酶 3 (Plk3)、HIF-1a、肿瘤发生和肿瘤血管生成之间的密切联系：Plk3 敲除小鼠在高龄时会在包括肺在内的多个组织中形成高度血管化的肿瘤。 Plk3-/- 小鼠胚胎成纤维细胞 (MEF) 表达更高水平的血管生成因子 VEGF。此外，Plk3 null MEF 在缺氧条件下表达升高水平的 HIF-1a。此外，我们最近的研究揭示了 Plk3 通过磷酸化对 HIF1a 的直接调节。因此，Plk3 是一种潜在的肿瘤抑制因子，可调节细胞缺氧和血管生成反应。基于这些先前的观察，我们假设 Plk3 通过抑制肺癌细胞的缺氧和血管生成反应，在肿瘤血管生成和镍诱导的肺部癌发生中发挥重要作用。我们提出三个具体目标来检验我们的假设： 目标 1. 研究缺氧和镍处理下肺癌细胞中 Plk3 蛋白水平和/或活性是否受到调节。目标 2. 确定 Plk3 在缺氧和镍处理下肺癌细胞产生促血管生成因子中的作用。目标 3. 研究 Plk3 在缺氧和镍处理下肺癌细胞增殖和存活中的作用。这些目标旨在回答两个基本问题： 1. Plk3 与肺癌进展相关吗？ 2. Plk3如何调控肺癌进展？拟议的研究应为进一步深入评估 Plk3 在肿瘤生物学中的功能以及 Plk3 作为肺癌治疗靶点的潜力奠定基础。这项研究还应有助于我们了解环境相关金属（例如镍）在肺癌中的潜在机制。 公共健康相关性：拟议的研究旨在探讨 Polo 样激酶 3 (Plk3) 在肺癌中的作用。肺癌是美国最常见的癌症类型之一，也是癌症相关死亡的主要原因。它也是最容易受到环境影响的癌症类型之一。拟议的研究将使用生化和分子/细胞生物学方法来研究 Plk3 在肺癌细胞模型中的功能。这项研究的结果应该为肺癌的生物学、环境相关镍金属如何影响肺癌的机制以及 Plk3 作为治疗靶点的潜力提供重要的新见解。