MicroRNA-based interventions to prevent progression from lung preneoplasia to adenocarcinoma

基于 MicroRNA 的干预措施可预防肺肿瘤前期发展为腺癌

• 批准号: 9379210
• 负责人: Roy S Herbst
• 金额: $ 20.76万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-26 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379210
• 关键词: Address; Adenocarcinoma; Alpha Cell; Atypical adenomatous hyperplasia; Automobile Driving; Benign; Binding; Biological Assay; Biological Markers; Cancer Etiology; Cancer Patient; Cells; Characteristics; Critical Pathways; DNA Sequence Alteration; Data; Detection; Development; Diagnosis; Dimensions; Disease; Epidermal Growth Factor Receptor; Event; Formalin; Frequencies; Gene Expression; Genetic Transcription; Goals; Growth; Heterogeneity; Inflammation; Inflammation Mediators; Inflammatory; Intervention; KRAS2 gene; Laboratories; Lesion; Link; Lung; Lung Adenocarcinoma; Lung Neoplasms; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular Profiling; Mutant Strains Mice; Neoplasms; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Nuclear; Oncogenic; Organoids; Paraffin Embedding; Pathology; Pathway interactions; Patients; Play; Premalignant; Premalignant Cell; Primary Neoplasm; Research; Role; Serum; Signal Pathway; Signal Transduction; Site; Specimen; Structure; Structure of parenchyma of lung; Survival Rate; TP53 gene; Techniques; Testing; Therapeutic; Tissues; Transcript; Transgenic Mice; Tumor Initiators; Tumor Tissue; Untranslated RNA; Up-Regulation; adenoma; base; cancer stem cell; genetic profiling; improved; inhibitor/antagonist; innovation; locked nucleic acid; mortality; mouse model; nanoparticle; neoplastic cell; novel; overexpression; precursor cell; prevent; programs; response; standard of care; stemness; treatment response; tumor; tumor initiation; tumor progression; tumorigenesis

PROJECT SUMMARY This proposal titled “MicroRNA-based interventions to prevent progression from lung preneoplasia to adenocarcinoma” is responsive to PQ1. Lung cancer is the most common cause of cancer-related mortality worldwide. Despite advances in detection and improvements to standard of care, the overall survival rate for lung cancer patients remains very low (5). This poor survival rate is probably due to the relatively advanced stage of the disease at diagnosis. If lung cancer could be identified and stopped at a preneoplastic stage prior to progression into advanced stage, we could improve the patients' survival. However, little is known about the biomarkers distinguishing preneoplasia from normal tissues and the molecules driving preneoplasia initiation and progression. Recent evidence has shown that intratumor cellular heterogeneity contributes to tumor initiation and progression of cancer, including lung cancer (6). Tumor-initiating cells (TICs) or cancer stem cells are a subpopulation of the bulk of tumor cells that can recapitulate the whole tumor's heterogeneous structures and functionally drive tumorigenesis. Nuclear factor-κB (NF-κB) is the key mediators of the inflammation response and has been recently been implicated as a driver of TICs (7). More recently, it has been found that inflammation can change expression of some microRNAs (miRNAs), including upregulation of oncogenic miR-21 (8). MiRNAs are non-coding RNAs belonging to a novel class of regulatory molecules that control gene expression by binding to complementary sites on multiple target messenger RNA (mRNA) transcripts simultaneously (9). However, the signaling events that link cancer stemness-related miRNAs to preneoplasia initiation and progression in inflammatory microenvironments remain to be charted. We hypothesize that inflammation induced miRNA dysregulation on TICs might drive preneoplasia initiation and progression in KRASmut or epidermal growth factor receptor (EGFRmut) lung adenocarcinoma patients, and that a deeper understanding of this may identify novel targets for miRNA-based therapeutics. In Aim 1, we will characterize a miRNA signature in preneoplasia in lung tissues. In Aim 2, we will investigate roles of miRNA inhibitors or mimics in preventing progression from preneoplasia to neoplasia in lung. At the conclusion of these studies, we will have generated a new tumor organoid model, developed miRNA therapeutics useful in curing preneoplasia and preventing malignant progression, as well as gained innovative information regarding roles of both TICs and the inflammatory niche in preneoplasia initiation and progression.

项目摘要 该提案标题为“基于microRNA的干预措施，以防止肺部肿瘤发展为 腺癌”对PQ1有反应。 肺癌是全球癌症相关死亡率的最常见原因。尽管检测进展 并提高了护理标准，肺癌患者的总生存率仍然很低（5）。 这种存活率差可能是由于诊断时疾病的相对晚期阶段。如果肺 癌症可以在进入晚期之前的肿瘤阶段识别并停止，我们 可以改善患者的生存。但是，对于区分质量核的生物标志物知之甚少 从正常组织和驱动质量肿瘤倡议和进展的分子中。最近的证据有 表明肿瘤内细胞异质性有助于癌症的肿瘤起步和进展，包括 肺癌（6）。肿瘤发射细胞（TICS）或癌干细胞是大部分肿瘤细胞的亚群 这可以概括整个肿瘤的异质结构并在功能上驱动肿瘤发生。核 因子-κB（NF-κB）是炎症反应的关键介体，最近已实施 抽动司机（7）。最近，已经发现炎症会改变某些的表达 microRNA（miRNA），包括致癌miR-21的上调（8）。 miRNA是非编码RNA 属于通过结合完成基因表达的新型调节分子 仅仅是多个目标信使RNA（mRNA）转录本上的位置（9）。但是，信号事件 将癌症与干性相关的miRNA与炎症性促进性和进展联系起来 微环境仍有待制定图表。我们假设炎症会诱导miRNA失调 抽动可能会推动Krasmut或表皮生长因子接收器中的主动性和进展 （egfrmut）肺腺癌患者，对此有更深入的了解可以识别出新的目标 用于基于miRNA的治疗。在AIM 1中，我们将表征肺前肿瘤中的miRNA签名 组织。在AIM 2中，我们将研究miRNA抑制剂或模仿在防止从 肺部肿瘤的肿瘤。这些研究结束时，我们将产生一个新的肿瘤 类器官模型，开发了miRNA疗法，可用于治愈质量肿瘤和预防恶性肿瘤 进展，并获得有关抽动和炎症性利基角色的创新信息 在肿瘤的倡议和进展中。