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 这项提案的标题是“基于MicroRNA的干预措施，以防止从肺癌前病变进展到 腺癌”对PQ 1有反应。 肺癌是全球癌症相关死亡的最常见原因。尽管在检测方面取得了进展 和护理标准的提高，肺癌患者的总体生存率仍然很低（5）。 这种低生存率可能是由于诊断时疾病的相对晚期。如果肺 癌症可以在进展到晚期之前的癌前阶段被识别和停止，我们 可以提高患者的生存率。然而，很少有人知道的生物标志物区分癌前病变 从正常组织和分子驱动癌前病变的开始和发展。最近的证据 显示肿瘤内细胞异质性有助于肿瘤的发生和癌症的进展，包括 肺癌6例。肿瘤起始细胞（TIC）或癌症干细胞是大量肿瘤细胞的亚群 它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质，最近被认为是 一个司机的交通信息中心（7）。最近，已经发现炎症可以改变一些 microRNAs（miRNAs），包括致癌miR-21的上调（8）。miRNAs是非编码RNA 属于一类新的调节分子，其通过结合互补的 同时在多个靶信使RNA（mRNA）转录本上定位（9）。然而，信号事件 将癌症干细胞相关miRNA与炎症性肿瘤前病变的发生和进展联系起来 微环境有待进一步研究。我们假设炎症诱导的miRNA表达失调可能与炎症相关。 TIC可能在KRASmut或表皮生长因子受体中驱动癌前病变的发生和进展 （EGFRmut）肺腺癌患者，并对此有更深入的了解可能会发现新的靶点 用于基于miRNA的治疗。在目标1中，我们将描述肺肿瘤前病变中的miRNA特征， 组织中在目标2中，我们将研究miRNA抑制剂或模拟物在预防肿瘤进展中的作用， 肺内的癌前病变至癌形成。在这些研究结束时，我们将产生一个新的肿瘤 类器官模型，开发了可用于治疗癌前病变和预防恶性肿瘤的miRNA疗法， 进展，以及获得有关TIC和炎症生态位作用的创新信息， 肿瘤前病变的发生和发展。