CHEMOPREVENTION WITH AEROSOLIZED LET-7 MICRORNA IN MOUSE MODELS OF NON-SMALL CELL LUNG CANCER (ADENOCARCINOMA AND SQUAMOUS CELL CARCINOMA)

该研究的目的是评估一种新的化学预防策略的有效性，该策略基于在小鼠肺癌发生实验模型中递送microRNA模拟物。MicroRNA是一类非编码的小分子RNA，在基因表达中起着转录后抑制因子和调节因子的作用。MicroRNA在人类癌症中严重失调，包括肺癌。在癌症中低表达的microRNA可以在功能上被分类为肿瘤抑制因子，而那些过度表达的则充当癌基因。let-7 microRNA家族是一个特征明确的肿瘤抑制因子家族，其基因映射到肺癌中经常缺失的不同染色体区域。Let-7 microRNA负调控多种癌基因，包括RAS、MYC和HMGA 2，以及细胞周期进程调节基因，如CDC 25 A、CDK 6和细胞周期蛋白D2。最近的结果报道了在A/J小鼠中抑制苯并[a]芘诱导的肺腺瘤体积达72%的雾化let-7 B模拟物的开发（Nano Lett.，19：2231-2242，2019），尽管该模型中的小鼠很少发生腺癌。由于肺腺癌和鳞状细胞癌约占所有人类癌症组织学亚型的80%，因此本任务指令的目的是确定1）雾化let-7 b是否对两种最常见的肺肿瘤亚型有效，以及2）雾化let-7 b至肺部是否可以最大限度地减少潜在的全身副作用。

The aim of the proposed study is to evaluate the efficacy of a novel chemopreventive strategy based on the delivery of microRNA mimetics in experimental models 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, and HMGA2, as well as cell-cycle progression regulator genes such as CDC25A, CDK6, and cyclin D2. Recent results have reported on the development of an aerosolized let-7B mimetic that inhibited benzo[a]pyrene-induced lung adenoma volume by 72% in A/J mice (Nano Lett., 19: 2231-2242, 2019), although mice in this model rarely develop adenocarcinomas. As lung adenocarcinomas and squamous cell carcinomas account for ~80% of all human cancer histological subtypes, the objectives of this Task Order are to determine 1) if aerosolized let-7b will be effective against the two most common lung tumor subtypes, and 2) if aerosolized delivery of let-7b to the lungs could minimize potential systemic side effects.