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未能成功治疗这种疾病。最近，let-7（一种称为microRNAs（miRNAs）的新的全球基因调节因子）水平低被确定为肺癌患者预后不良的预测因子。在这项工作中，我们建议测试的假设，miRNA let-7是一种肿瘤抑制剂在肺，可能是一种新的，但潜在的强大的方法来治疗和/或敏感肺癌细胞毒性治疗。在本提案的具体目标1中，我们将基于以下发现来检验let-7确实是肺中的肿瘤抑制因子并且可用于逆转肺细胞生长的假设：1）在C. elegans过表达let-7可以抑制RAS中的激活突变2）let-7在体外抑制人RAS并且在人肺癌中处于低水平，和3）let-7在体外和体内过表达可以逆转肺细胞生长（初步数据）。我们将进一步测试let-7可以在肺癌小鼠模型中减少或逆转活化K-Ras的致癌作用的假设。在特定目标2中，我们将检验let-7操作可用于影响细胞对细胞毒性治疗的反应的假设。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操作可以影响照射后的细胞存活。我们将进一步验证这些发现的机制，let-7参与对其他细胞毒性治疗的反应，以及在肺癌异种移植和小鼠模型中let-7体内操作细胞毒性治疗后影响肺癌细胞存活的潜力。这些研究可能是用let-7治疗肺癌的第一步。我们认为，我们对哺乳动物let-7的分析，可能是人类癌症基因的主要调节因子，有可能大大提高我们对肺癌的理解。总的来说，本提案中概述的工作应该阐明肺癌发展和治疗反应的机制，并有可能为肺癌患者提供一种新的治疗方法，目前肺癌患者是一个缺乏有效治疗方法的临床群体。我们认为，由于我们提出的干预措施是基于天然的miRNA指导的细胞过程，它增加了成功的机会，毒性有限。 公共卫生相关性： 了解microRNA（最近发现的遗传调节因子）作为新型癌症疗法本身或作为当前癌症疗法的增强剂的潜力将是癌症研究的巨大进步。在这项提案中，我们计划进行实验，以了解如何利用这些天然的遗传生长抑制因子，以将其应用于癌症治疗。

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. PUBLIC HEALTH RELEVANCE: Understanding the potential of microRNAs (recently discovered genetic regulators) as novel cancer therapies themselves or as enhancers of current cancer therapies would be an enormous advance in cancer research. In this proposal we plan experiments to learn how to harness these natural genetic growth repressors to work towards their application to cancer therapy.