MutT Homolog 1 as a Novel Mediator of RAS Oncogene-Induced Pro-Malignant Pathways

MutT 同源物 1 作为 RAS 癌基因诱导的恶性途径的新型介体

基本信息

批准号：
8481679
负责人：
Priyamvada Rai
金额：
$ 31.84万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8481679
关键词：
8-oxo-dGTP Address Adenocarcinoma Affect Agar Animal Model Animals Biological Markers Breast Breast Cancer Cell Cancer cell line Cell Aging Cell Death Cell Line Cell Proliferation Cells Characteristics Chronic DNA DNA Damage Data Development Diagnostic Disease Drug Targeting Effector Cell Epithelial Epithelial Cells Evaluation Gender Goals HRAS gene Homologous Gene Human KRAS2 gene Laboratories Lead Lung Lung Neoplasms Maintenance Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Mesenchymal Molecular Morphology Mutation Normal Cell Normal tissue morphology Oncogenes Oncogenic Outcome Oxidation-Reduction Oxidative Stress Pathway interactions Process Production Proteins Publishing Reactive Oxygen Species Regulatory Pathway Relative (related person)Reporting Research Resistance Role Signal Transduction Staining method Stains Stress Structure of parenchyma of lung Testing Therapeutic Tissues Treatment Efficacy Tumor Cell Line Tumor Tissue Tumorigenicity Up-Regulation Validation Work base cell transformation cell type dGTPase human data in vivo innovation knockout animal lung Carcinoma melanocyte mouse model mutant neoplastic cell novel outcome forecast overexpression oxidative DNA damage pre-clinical prevent prognostic public health relevance response therapeutic target trait tumor tumor xenograft tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Approximately 25% of all tumor types sustain oncogenic RAS mutations. Oncogenic RAS activation confers multiple tumor-promoting characteristics including unrestrained proliferation, survival signaling, and increased invasiveness. These features are mediated by oncogene-induced reactive oxygen species (ROS). However oncogenic ROS also lead to DNA damage, which is a major effector of cell death and cell senescence, two common therapeutic outcomes. Hence, RAS-transformed cells must evade ROS- associated damaging effects without entirely eliminating ROS production. Studies have shown that proteins that can effectively suppress ROS-associated anti-tumorigenic functions promote RAS-mediated tumor formation. The mammalian 8-oxo-dGTP triphosphatase, human MutT Homolog 1(MTH1) is unique in that its functionality inhibits oxidative DNA damage but does not directly affect ROS levels. Studies from our laboratory as well as others indicate unusually high expression of MTH1 in cancers associated with activating RAS mutations. Our published and preliminary data further show that oncogenic RAS expression upregulates MTH1 protein levels in a number of different cell types. We also recently reported MTH1 overexpression in normal cells prevents oncogenic RAS-induced oxidative DNA damage and cellular senescence, a critical barrier against oncogene-induced tumorigenesis. Conversely, we found MTH1 suppression selectively affects proliferation and survival pathways in the RAS-transformed counterparts in isogenic breast cancer cell lines. Our preliminary data further indicate that MTH1 suppression affects transformation efficiency, xenograft tumor formation, pro-survival pathways and invasive morphology in oncogenic RAS-transformed cells. Thus our central hypothesis is that elevated MTH1 expression is a critical adaptive change that functionally uncouples the tumor-promoting effects of oncogenic ROS from their damaging effects, thus enhancing proliferation and survival of RAS-transformed cells. The overall goal of this proposal is: 1) to fully characterize the molecular and cellular implications of MTH1 upregulation on oncogenic RAS-induced mechanisms of tumor development and promotion, and 2) to assess the in vivo effects of abrogating MTH1 function in an activated KRAS mouse model of lung cancer. Our studies will provide mechanistic validation for targeting MTH1 in RAS-transformed tumors as a means to enhance therapeutic efficacy by shifting cellular response away from pro-proliferative and pro-survival mechanisms and towards cell senescence or cell death.

描述（由申请人提供）：大约 25% 的所有肿瘤类型都存在致癌 RAS 突变。致癌 RAS 激活赋予多种促肿瘤特征，包括不受限制的增殖、生存信号传导和侵袭性增加。这些特征是由癌基因诱导的活性氧（ROS）介导的。然而，致癌活性氧也会导致 DNA 损伤，这是细胞死亡和细胞衰老（两种常见治疗结果）的主要效应因素。因此，RAS 转化的细胞必须逃避 ROS 相关的破坏作用，而不完全消除 ROS 的产生。研究表明，能够有效抑制ROS相关抗肿瘤功能的蛋白质可以促进RAS介导的肿瘤形成。哺乳动物 8-oxo-dGTP 三磷酸酶、人 MutT 同源物 1 (MTH1) 的独特之处在于，其功能可抑制氧化 DNA 损伤，但不会直接影响 ROS 水平。我们实验室以及其他实验室的研究表明，MTH1 在与激活 RAS 突变相关的癌症中异常高表达。我们发表的初步数据进一步表明，致癌 RAS 表达上调许多不同细胞类型中的 MTH1 蛋白水平。我们最近还报道了正常细胞中 MTH1 的过度表达可以防止致癌 RAS 诱导的氧化 DNA 损伤和细胞衰老，这是防止致癌基因诱导的肿瘤发生的关键障碍。相反，我们发现 MTH1 抑制选择性地影响同基因乳腺癌细胞系中 RAS 转化对应物的增殖和生存途径。我们的初步数据进一步表明，MTH1 抑制会影响致癌 RAS 转化细胞的转化效率、异种移植肿瘤形成、促生存途径和侵袭形态。因此，我们的中心假设是，MTH1 表达升高是一种关键的适应性变化，它在功能上将致癌 ROS 的肿瘤促进作用与其破坏作用分开，从而增强 RAS 转化细胞的增殖和存活。该提案的总体目标是：1) 全面表征 MTH1 上调对致癌 RAS 诱导的肿瘤发展和促进机制的分子和细胞影响，2) 评估在激活的 KRAS 中废除 MTH1 功能的体内影响小鼠肺癌模型。我们的研究将为RAS转化肿瘤中靶向MTH1提供机制验证，作为一种通过将细胞反应从促增殖和促生存机制转向细胞衰老或细胞死亡来增强治疗效果的手段。