IGF::OT::IGF LUNG CANCER CHEMOPREVENTION BY MICRORNA DELIVERY

肺癌是全球癌症相关死亡的主要原因。尽管新兴的成像技术和新开发的靶向化疗药物改善了最初的治疗反应，使早期诊断成为可能，但在过去的30年里，肺癌患者的总体5年生存率一直保持在令人沮丧的10%-15%。尽管与吸烟有关的疾病的主要预防策略是戒烟，但即使在戒烟后15年，患肺癌的风险仍然显著高于不吸烟的人。因此，开发能够防止肺部病变发展为恶性肿瘤的化学预防策略将降低这种致命疾病造成的死亡率和发病率。吸烟者和戒烟者构成了一组容易识别的肺癌高危人群，他们将受益于化学预防疗法的干预。 这项研究的目的是评估一种基于传递microRNA模拟物的新的化学预防策略在小鼠肺癌发生的实验模型中的有效性。MicroRNAs是一种非编码的小RNA，作为转录后抑制因子和基因表达的调节因子。在包括肺癌在内的人类癌症中，microRNAs的表达严重失调。在癌症中表达不足的microRNAs在功能上可以被归类为肿瘤抑制因子，而那些过度表达的microRNAs则充当癌基因。Let-7microRNA家族是一个具有良好特性的肿瘤抑制基因家族，其基因映射到肺癌中经常缺失的不同染色体区域。Let-7microRNAs负性调控多种癌基因，包括ras、myc、HMGA2和细胞周期调控基因，如cdc25a、CDK6和细胞周期蛋白D2。 。 因此，microRNA递送被认为是肺癌治疗的一种新策略。Kumar等人之前的研究。(自然科学教授)105：3903-8,2008)和Trang等人。(致癌基因29：1580-7,2010)的研究表明，经气管或鼻腔暴露于表达let-7 miRNA模拟物的病毒载体可降低肺癌的负担。然而，这些研究是在基因工程小鼠模型中进行的，这些模型发展出与治疗方案更相关的高度侵袭性肿瘤。此外，Kumar et al.注意到出现了一些对let-7 miRNA具有耐药性的肿瘤。因此，由于癌细胞基因组的不稳定性，改变的microRNAs的模式不断变化，这一事实可能限制了这种方法的成功。在健康和癌前细胞中，microRNA表达的变化可能不那么不稳定，更有可能通过药物治疗而逆转。 因此，在利用与烟草烟雾诱导的疾病有关的化学致癌物的小鼠化学致癌模型中测试let-7miRNA对于确定这些药物在预防策略中的潜在使用将是重要的。该模型开发出潜伏期较长的肿瘤，并允许在肿瘤启动和进展的最早阶段评估制剂效果。重要的是开发一种鼻腔或气雾剂给药系统，随后可以测试microRNA给药的安全性和有效性，目的是通过阻止肺癌发生过程的进展来预防肺癌。

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite improvements in early diagnosis that were made possible by emerging imaging technologies and newly developed targeted chemotherapeutic agents that improve initial treatment responses, the overall 5-year survival for lung cancer patients has remained a dismal 10-15% over the past 3 decades. Although the primary preventive strategy for smoke related diseases is quitting smoking, even after smoking cessation the risk of developing lung cancer remains significantly higher than in non-smokers for 15 years. Thus, the development of chemopreventive strategies that could prevent the progression of lung lesions to malignant cancers would reduce the mortality and morbidity resulting from this deadly disease. The population of tobacco smokers and ex-smokers constitutes a readily identifiable group of individuals at risk for lung cancer who would benefit from intervention with chemopreventive regimens. The aim of the proposed study is to evaluate the efficacy of a novel chemopreventive strategy based on the delivery of microRNA mimetics in an experimental model of lung carcinogenesis in mice. MicroRNAs are noncoding small RNAs acting as post-transcriptional repressors and regulators of gene expression. MicroRNAs are grossly dysregulated in human cancers, including lung cancer. The microRNAs that are under-expressed in cancer can be functionally classified as tumor-suppressors while those that are over-expressed act as oncogenes. The let-7 microRNA family is a well characterized family of tumor suppressors whose genes map to different chromosomal regions that are frequently deleted in lung cancer. Let-7 microRNAs negatively regulate multiple oncogenes, including ras, myc, hmga2, and cell-cycle progression regulator genes, such as cdc25a, cdk6, and cyclin D2. . Accordingly, microRNA delivery has been proposed as a new strategy for lung cancer therapy. Previous studies by Kumar et al. (Proc.Natl.Acad.Sci. 105: 3903-8, 2008) and Trang et al. (Oncogene 29: 1580-7, 2010) have shown that intratracheal or intranasal exposure of genetically engineered mice to viral vectors expressing let-7 miRNA mimetics resulted in reduced lung tumor burdens. However, these studies were done in genetically engineered mouse models that developed highly aggressive tumors more relevant for a treatment regimen. In addition, Kumar et al. noted that some tumors emerged that were resistant to the let-7 miRNA. The success of this approach may thus be limited by the fact that the patterns of altered microRNAs continuously change due to the instability of cancer cell genome. In healthy and premalignant cells, the alterations in microRNA expression may be less unstable and more likely to be reversible with agent treatment. Thus, testing of let-7 miRNA in murine models of chemical carcinogenesis utilizing chemical carcinogens implicated in tobacco smoke-induced disease would be important for determining the potential use of these agents in prevention strategies. This model develops tumors with a longer latency and allows an assessment of agent effects at the earliest stages of tumor initiation and progression. It will be important to develop an intranasal or aerosol delivery system that could be subsequently tested for safety and efficacy of microRNA administration aimed at preventing lung cancer by blocking the progression of the carcinogenesis process.