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

描述(由申请人提供)：大约25%的肿瘤类型存在致癌的RAS突变。致癌RAS激活具有多种促肿瘤特性，包括不受抑制的增殖、生存信号和增加的侵袭性。这些特征是由癌基因诱导的活性氧(ROS)介导的。然而，致癌的ROS也会导致DNA损伤，DNA损伤是细胞死亡和细胞衰老的主要影响因素，这是两种常见的治疗结果。因此，RAS转化的细胞必须避免与ROS相关的破坏效应，而不是完全消除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。哺乳动物的8-oxo-dGTP三磷酸酶，人突变同源基因1(MTH1)的独特之处在于它的功能是抑制DNA氧化损伤，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，MTH1在与激活RAS突变相关的癌症中异常高表达。我们已发表的和初步的数据进一步表明，致癌的RAS表达上调了许多不同类型的细胞中MTH1的蛋白水平。我们最近还报道，在正常细胞中过表达MTH1可以防止致癌RAS诱导的DNA氧化损伤和细胞衰老，这是对抗癌基因诱导的肿瘤发生的关键屏障。相反，我们发现在同基因乳腺癌细胞系中，MTH1抑制选择性地影响RAS转化的对应物的增殖和生存途径。我们的初步数据进一步表明，MTH1抑制影响致癌RAS转化细胞的转化效率、异种移植瘤的形成、促生存途径和侵袭形态。因此，我们的中心假设是，MTH1的高表达是一种关键的适应性变化，它在功能上将致癌ROS的促肿瘤作用与其破坏作用分开，从而促进RAS转化细胞的增殖和存活。这项建议的总体目标是：1)充分表征MTH1上调在致癌RAS诱导的肿瘤发生和促进机制中的分子和细胞意义，以及2)评估在活化的KRAS小鼠肺癌模型中取消MTH1功能的体内效应。我们的研究将为靶向RAS转化肿瘤的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提高治疗效果的手段。

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.