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

描述（由申请人提供）：所有肿瘤类型中约25%存在致癌RAS突变。致癌性RAS激活赋予多种肿瘤促进特征，包括不受限制的增殖、存活信号传导和增加的侵袭性。这些特征由癌基因诱导的活性氧（ROS）介导。然而，致癌ROS也导致DNA损伤，这是细胞死亡和细胞衰老的主要效应子，这是两种常见的治疗结果。因此，RAS转化的细胞必须避免ROS相关的损伤作用，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，人类MutT同系物1（MTH 1）的独特之处在于其功能抑制氧化DNA损伤，但不直接影响ROS水平。我们实验室和其他实验室的研究表明，MTH 1在与激活RAS突变相关的癌症中异常高表达。我们发表的和初步的数据进一步表明，致癌RAS表达上调MTH 1蛋白水平在许多不同的细胞类型。我们最近还报道了MTH 1在正常细胞中的过表达可以防止致癌RAS诱导的氧化DNA损伤和细胞衰老，这是对抗癌基因诱导的肿瘤发生的关键屏障。相反，我们发现MTH 1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存活途径。我们的初步数据进一步表明，MTH 1抑制影响转化效率，异种移植肿瘤形成，促生存途径和致癌RAS转化细胞的侵袭性形态。因此，我们的中心假设是，MTH 1表达升高是一个关键的适应性变化，从功能上解偶联致癌活性氧的肿瘤促进作用，从他们的破坏作用，从而提高RAS转化细胞的增殖和生存。 该提案的总体目标是：1）充分表征MTH 1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，以及2）评估在活化的KRAS肺癌小鼠模型中废除MTH 1功能的体内作用。我们的研究将为RAS转化肿瘤中靶向MTH 1提供机制验证，作为通过将细胞反应从促增殖和促存活机制转移到细胞衰老或细胞死亡来增强治疗功效的手段。

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.