Project 4: NOX1 Involvement In Colon Cancer

项目 4：NOX1 参与结肠癌

• 批准号: 8099689
• 负责人: John David Lambeth
• 金额: $ 13.83万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099689
• 关键词: 1-Phosphatidylinositol 3-Kinase; Age; Animals; Apoptosis; Cause of Death; Cell model; Cells; Cessation of life; Colon; Colon Carcinoma; Colorectal Neoplasms; DNA Damage; Enzymes; Event; Family; Genetic Transcription; Growth; Human; Intestinal Cancer; Intestinal Neoplasms; Intestines; Knock-out; Knockout Mice; Link; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Mitosis; Molecular; Mus; Mutation; NADPH Oxidase; NF-kappa B; Neoplasms; Normal tissue morphology; Nox enzyme; Oncogenic; Oxidants; Oxidative Stress; Pathway interactions; Play; Population; Protein Tyrosine Phosphatase; Protein p53; Reactive Oxygen Species; Rectum; Role; Signal Pathway; Signal Transduction; Source; System; TP53 gene; Testing; Tissues; Tyrosine Phosphorylation; United States; angiogenesis; base; genetic regulatory protein; intestinal epithelium; mouse model; mutant; novel; overexpression; oxidant stress; response; transcription factor; tumor; tumor initiation; tumorigenesis; villin

Nox1 Oxidant Stress, Ras And Colon Cancer" The NADPH-oxidase Nox1 generates reactive oxygen species (ROS) that function through signaling pathways to activate mitogenic growth and angiogenesis. Nox1 is overexpressed in -60-70% of early human colon cancers, consistent with a role in tumorigenesis. Based on cell model studies, we hypothesize that Nox1 overexpression in human colon cancers can result from induction of Nox1 transcription by activated KRas. Human intestinal tumors vs. control tissue will be characterized to establish whether Nox1 overexpression is linked to oncogenic mutations in K-Ras and/or to inactivating mutations in the tumor suppressors p53 and ARC. The extent to which Nox1 overexpression in tumors is associated with NFkappaB activation, Cox2 overexpression and activation of growth-related signaling pathways (MARK, PI 3- kinase) will also be evaluated. To evaluate directly the causal relationships among K-Ras oncogenic mutation, Nox1 overexpression, and intestinal cancer, we previously developed Nox1-overexpressing and Nox1 -knockout mice. By crossing villin K-RasV12 mice with Nox1-knockout and Nox1-overexpressing animals, we will test whether Nox1 mediates V12-Ras-directed tumorigenesis. By investigating Nox1 expression, mutation of tumor suppressors (p53 and ARC) and activation of growth-associated signaling pathways (Akt/PKB, ERK1,2, JNK) in tumors and adjacent normal tissue, we will determine molecular events relevant to tumor initiation and progression. The mechanisms by which Nox1 regulates mitogenic growth will be further investigated by evaluating activation of NF-kappaB and the induction/activation of Cox2. We will evaluate collaboratively with other projects the role of Nox1 in the induction of the DNA damage response in the tumor initiation/progression pathway. We will also investigate the hypothesis that Nox1-derived ROS stimulates mitogenic growth by inhibiting protein tyrosine phosphatases, leading to a increased tyrosine phosphorylation levels of important mitogenic regulatory proteins. These studies will provide novel information regarding the role of Nox1 in gastrointestinal cancers, its relationship to oncogenic mutations in K-Ras, and the mitogenic signaling systems utilized by Ras and Nox1.

Nox 1氧化应激、Ras和结肠癌” NADPH氧化酶Nox 1产生活性氧（ROS），通过信号传导发挥作用 激活促有丝分裂生长和血管生成的途径。Nox 1在约60 - 70%的早期人类肿瘤中过表达。 结肠癌，与肿瘤发生中的作用一致。基于细胞模型研究，我们假设， 人结肠癌中的Nox 1过表达可能是由激活的KRas诱导Nox 1转录引起的。 将表征人肠肿瘤与对照组织，以确定Nox 1 过表达与K-Ras的致癌突变和/或肿瘤中的失活突变有关 抑制子p53和ARC。肿瘤中Nox 1过表达的程度与NF κ B相关 活化，Cox 2过表达和生长相关信号通路的活化（MARK，PI 3- 激酶）也将被评估。目的：直接评价K-Ras致癌基因间的因果关系， 突变，Nox 1过表达，和肠癌，我们以前开发的Nox 1过表达， Nox 1基因敲除小鼠。通过将绒毛蛋白K-RasV 12小鼠与Nox 1敲除和Nox 1过表达小鼠杂交， 动物，我们将测试Nox 1是否介导V12-Ras导向的肿瘤发生。通过研究Nox 1 肿瘤抑制因子（p53和ARC）的表达、突变和生长相关信号的激活 在肿瘤和邻近正常组织中的Akt/PKB，ERK 1，2，JNK通路，我们将确定分子事件 与肿瘤的发生和发展有关。Nox 1调节有丝分裂生长的机制将 通过评估NF-κ B的活化和Cox 2的诱导/活化来进一步研究。我们将 与其他项目合作评估Nox 1在诱导DNA损伤反应中的作用， 肿瘤发生/发展途径。我们还将研究Nox 1衍生的ROS 通过抑制蛋白酪氨酸磷酸酶刺激促有丝分裂生长，导致酪氨酸磷酸酶活性增加， 重要的促有丝分裂调节蛋白的磷酸化水平。这些研究将提供新的 关于Nox 1在胃肠道癌症中的作用，其与肿瘤基因突变的关系， K-Ras，以及Ras和Nox 1所利用的促有丝分裂信号系统。