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%的肿瘤类型维持致癌RAS突变。致癌RAS激活具有多种肿瘤促进特征，包括无限制的增殖、生存信号和侵袭性增加。这些特征是由癌基因诱导的活性氧（ROS）介导的。然而，致癌ROS也会导致DNA损伤，这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ROS相关的损伤效应，而不完全消除ROS的产生。研究表明，能够有效抑制ras相关抗肿瘤功能的蛋白促进ras介导的肿瘤形成。哺乳动物8-oxo-dGTP三磷酸酶，人类MutT同源物1（MTH1）的独特之处在于其功能抑制DNA氧化损伤，但不直接影响ROS水平。我们实验室的研究以及其他研究表明，在与RAS突变激活相关的癌症中，MTH1的异常高表达。我们发表的和初步的数据进一步表明，在许多不同的细胞类型中，致癌的RAS表达上调MTH1蛋白水平。我们最近也报道了正常细胞中MTH1的过表达可以防止ras诱导的致癌DNA氧化损伤和细胞衰老，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ras转化的乳腺癌细胞系的增殖和存活途径。我们的初步数据进一步表明，MTH1抑制会影响致癌ras转化细胞的转化效率、异种移植物肿瘤的形成、促生存途径和侵袭形态。因此，我们的中心假设是，MTH1表达的升高是一个关键的适应性变化，它在功能上将致癌ROS的促肿瘤作用与它们的破坏性作用分离开来，从而增强ras转化细胞的增殖和存活。本课题的总体目标是：1)全面表征MTH1上调对ras诱导的肿瘤发生和促进机制的分子和细胞意义；2)在激活的KRAS肺癌小鼠模型中评估取消MTH1功能的体内效应。我们的研究将为靶向MTH1治疗ras转化肿瘤提供机制验证，通过将细胞反应从促增殖和促生存机制转变为细胞衰老或细胞死亡机制来提高治疗效果。

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.