Let-7 microRNAs in Lung Cancer: Altering Growth and Radioresistance

描述(由申请人提供)： 肺癌是美国癌症死亡的主要原因，现有的治疗方法在绝大多数病例中都未能成功治疗这种疾病。最近，LET-7水平低，属于一种名为microRNAs(MiRNAs)的新的全球基因调控因子，被认为是肺癌患者预后不良的预测因子。在这项工作中，我们建议检验这一假设，即miRNA let-7是肺部的一种肿瘤抑制因子，可能是一种新的但潜在的有效方法来治疗肺癌和/或使肺癌对细胞毒治疗敏感。在本提案的具体目标1中，我们将测试let-7确实是肺中的肿瘤抑制因子并可用于逆转肺细胞生长的假设，基于以下发现：1)在线虫中过表达let-7可抑制RAS的激活突变；2)let-7在体外抑制人RAS，并在人肺癌中处于低水平；3)let-7在体外和体内过表达可逆转肺细胞生长(初步数据)。我们将进一步测试let-7可以减少或逆转激活K-RAS在小鼠肺癌模型中的致癌作用的假设。在特定的目标2中，我们将测试let-7操作可以用来影响细胞对细胞毒治疗的反应的假设。我们之前已经证明，let-7参与了肺细胞对放射治疗的反应，并且let-7的操作可以影响照射后细胞的存活。我们将进一步验证这些发现的机制，let-7参与其他细胞毒治疗的反应，以及在异种移植瘤和小鼠肺癌模型中，let-7操纵细胞毒治疗后影响肺癌细胞存活的可能性。这些研究可能是涉及let-7的肺癌治疗的第一步。我们假设，我们对哺乳动物let-7的分析有可能极大地提高我们对肺癌的理解。let-7可能是人类癌症基因的主要调节因子。总体而言，该提案中的工作大纲应该有助于阐明肺癌的发展和治疗反应的机制，并有可能为肺癌患者带来一种新的治疗方法，目前肺癌患者是一个缺乏有效治疗的临床群体。我们认为，由于我们建议的干预是基于自然的miRNA指导的细胞过程，它以有限的毒性增加了成功的机会。

DESCRIPTION (provided by applicant): Lung cancer is the major cause of cancer deaths in the US, and existing therapies fail to treat this disease successfully in the overwhelming majority of cases. Recently, having low levels of let-7, a member of a new class of global gene regulators called microRNAs (miRNAs), was identified as a predictor of a poor outcome in lung cancer patients. In this work we propose to test the hypothesis that the miRNA let-7 is a tumor suppressor in the lung and may be a novel but potentially powerful approach to treat and/or sensitize lung cancer to cytotoxic therapy. In Specific Aim 1 of this proposal we will test the hypothesis that let-7 is indeed a tumor suppressor in the lung and could be used to reverse lung cell growth based on the findings that: 1) In C. elegans over-expression of let-7 can suppress the activating mutations in RAS 2) let-7 suppresses human RAS in vitro and is at low levels in human lung cancer, and 3) let-7 overexpression in vitro and in vivo can reverse lung cell growth (preliminary data). We will further test the hypothesis that let-7 can reduce or reverse the oncogenic effects of activate K-Ras in a mouse model of lung cancer. In Specific Aim 2 we will test the hypothesis that let-7 manipulation can be used to impact the cellular response to cytotoxic therapy. We have previously shown that let-7 is involved in the response to radiotherapy in lung cells, and that let-7 manipulation can impact cell survival post-irradiation. We will further validate the mechanism of these findings, the involvement of let-7 in the response to other cytotoxic therapies, and the potential of impacting lung cancer cell survival post-cytotoxic therapy with let-7 manipulation in vivo in xenograft and mouse models of lung cancer. These studies could be the first steps towards a lung cancer therapy involving let-7. We posit that our analysis of mammalian let-7, which may be a master regulator of human cancer genes, has the potential to drastically improve our understanding of lung cancer. Overall, the work outlines in this proposal should shed light on the mechanisms of lung cancer development and response to therapy, and has the potential to lead to a novel treatment approach for lung cancer patients, currently a clinical group lacking effective therapies. We feel that because our proposed intervention is based upon a natural miRNA-directed cellular process, it has enhanced chance for success with limited toxicity.