Plk3 in nickel-induced lung carcinogenesis

Plk3 在镍诱导的肺癌发生中的作用

基本信息

批准号：
8874983
负责人：
DAZHONG XU
金额：
$ 23.08万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-18 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8874983
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Air Pollutants Americas Angiogenic Factor Animals Biochemical Biological Biology Cancer Etiology Carcinogens Cell Proliferation Cell Survival Cell physiology Cells Cessation of life Cytokine-Inducible Kinase Elderly Embryo Environmental Carcinogens Environmental Exposure Epigenetic Process Epithelial Cells Evaluation Exposure to Fibroblasts Growth Health Human Human Development Hypoxia Incidence Knockout Mice Light Link Lung Lung Neoplasms Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Metabolic Molecular Molecular and Cellular Biology Mus Mutation Nickel PLK3 gene PTEN gene Pathway interactions Process Proteins Regulation Reporting Research Risk Role Serine Signal Pathway Testing Tissues Transgenic Mice Tumor Angiogenesis Tumor Biology Tumor Suppressor Proteins Xenograft Model airborne carcinogen angiogenesis base cancer type cell growth cell transformation design hypoxia inducible factor 1 lung Carcinoma lung carcinogenesis lung tumorigenesis metaplastic cell transformation mouse model novel response therapeutic target tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Environmental exposures to airborne carcinogens are the main etiological factors for lung cancers. Air pollutants such as nickel compounds pose significant risk for developing lung cancer in human. HIF-1 is a master regulator of the cellular hypoxic responses that promotes angiogenesis and cellular adaptation to hypoxia. It is also an important mediator of tumorigenesis and tumor progression. PTEN is an important tumor suppressor that negatively regulates the PI3K signaling pathway. The PI3K pathway mediates cell proliferation, growth, and survival thereby promoting tumorigenesis and tumor progression. Mutations and/or deletions of PTEN are frequently associated with human cancers. Thus, regulators of HIF-1� and PTEN are of great importance in tumor biology. Previous research has linked Plk3 to tumorigenesis and tumor progression. Our recent studies revealed direct regulations of HIF-1� and PTEN by Plk3. These findings suggest that Plk3 may act as a tumor suppressor that inhibits tumorigenesis and tumor progression by reducing cellular proliferative, growth, survival, and angiogenic processes. Of note, reduced expression of Plk3 has been reported in lung carcinomas. Based on these findings, we hypothesize that Plk3 suppresses nickel-induced tumorigenesis and tumor progression in the lung through regulating HIF-1 and PTEN. We propose two Specific Aims to test this hypothesis: Aim 1. To define the role of Plk3 in nickel-induced lung tumorigenesis in mouse models. Aim 2. To determine the role of Plk3 in nickel-induced lung epithelial cell transformation and tumor formation. These Specific Aims are designed to answer two basic questions: 1. Is Plk3 a significant player in lung carcinogenesis induced by nickel compounds? 2. How may Plk3 regulate lung tumorigenesis induced by nickel compounds through the newly identified regulatory mechanisms? We will combine approaches using mouse models and molecular/cellular biology to address these questions. This study should significantly advance our understanding of lung carcinogenesis in response to nickel compounds, the biology of Plk3, as well as the basic regulation of HIF-1� and PTEN. It will also serve as an initial evaluation of the potential of Plk3 as a therapeutic target.

描述（由申请人提供）：环境中暴露于空气中的致癌物质是肺癌的主要病因，镍等空气污染物对人类罹患肺癌具有重大风险。HIF-1 是细胞缺氧反应的主要调节因子。促进血管生成和细胞对缺氧的适应，它也是肿瘤发生和肿瘤进展的重要介质，是负向调节 PI3K 信号传导的重要肿瘤抑制因子。 PI3K 通路介导细胞增殖、生长和存活，从而促进肿瘤发生和肿瘤进展。因此，HIF-1� 和 PTEN 的调节因子在肿瘤中非常重要。先前的研究已将 Plk3 与肿瘤发生和肿瘤进展联系起来。我们最近的研究揭示了 Plk3 对 HIF-1 和 PTEN 的直接调节，这些发现表明 Plk3 可能充当抑制肿瘤的抑制剂。通过减少细胞增殖、生长、存活和血管生成过程来抑制肿瘤发生和肿瘤进展值得注意的是，据报道，肺癌中 Plk3 的表达降低，基于这些发现，我们发现 Plk3 可以抑制镍诱导的肿瘤发生和肿瘤进展。我们提出了两个具体目标来检验这一假设：目标 1. 确定 Plk3 在小鼠模型中镍诱导的肺部肿瘤发生中的作用。 2. 确定 Plk3 在镍诱导的肺上皮细胞转化和肿瘤形成中的作用这些具体目标旨在回答两个基本问题： 1. Plk3 是否在镍化合物诱导的肺癌发生中发挥重要作用？ Plk3 通过新发现的调节机制调节镍化合物诱导的肺部肿瘤发生？我们将结合使用小鼠模型和分子/细胞生物学的方法来解决这些问题。这项研究将显着增进我们对肺部的理解。镍化合物的致癌作用、Plk3 的生物学特性以及 HIF-1� 和 PTEN 的基本调节也将作为 Plk3 作为治疗靶点潜力的初步评估。