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：
8657017
负责人：
Priyamvada Rai
金额：
$ 30.9万
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/8657017
关键词：
8-oxo-dGTP Address Adenocarcinoma Affect Agar Animal Model Animals Biological Markers Breast Cancer Cell Breast Epithelial Cells 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）：所有肿瘤类型的大约25％维持致癌RAS突变。致癌性RAS激活赋予了多个促进肿瘤的特征，包括无限的增殖，存活信号传导和增加的侵入性。这些特征是由癌基因诱导的活性氧（ROS）介导的。然而，致癌性ROS也会导致DNA损伤，这是细胞死亡和细胞衰老的主要效应因子，这是两个常见的治疗结果。因此，RAS转化的细胞必须逃避与ROS的破坏作用，而不会完全消除ROS产生。研究表明，可以有效抑制与ROS相关的抗肿瘤功能的蛋白质促进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）是独一无二的，因为其功能抑制了氧化DNA损伤，但不会直接影响ROS水平。我们实验室以及其他研究的研究表明，与激活RAS突变有关的癌症中MTH1的表达异常高。我们发表的初步数据进一步表明，致癌性RAS表达在许多不同的细胞类型中上调了MTH1蛋白水平。我们最近还报道了正常细胞中MTH1的过表达，可防止致癌性RAS诱导的氧化性DNA损伤和细胞衰老，这是抗癌基因诱导的肿瘤发生的关键屏障。相反，我们发现MTH1抑制选择性地影响了等源性乳腺癌细胞系中RAS转化的对应物中的增殖和存活途径。我们的初步数据进一步表明，MTH1抑制会影响致癌性RAS转化细胞的转化效率，异种移植肿瘤的形成，促寿命途径和侵入性形态。因此，我们的中心假设是，升高的MTH1表达是一种关键的适应性变化，在功能上取消了致癌ROS的肿瘤促进作用，从其破坏性作用中增强了RAS转化细胞的增殖和存活。该提案的总体目标是：1）完全表征MTH1上调对肿瘤发育和促进的致癌Ras诱导机制的分子和细胞的意义，以及2）评估在活化的肺癌活化KRAS小鼠模型中，消除MTH1功能的体内影响。我们的研究将提供机械验证，以靶向RAS转化的肿瘤中的MTH1，以此作为通过将细胞反应从促生殖和促生存性机制转移到细胞衰老或细胞死亡的方法，从而增强治疗疗效的手段。