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

项目总结 这项题为“基于microRNA的干预措施，以防止从肺上皮癌进展到 腺癌“对PQ1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步 随着护理水平的提高，肺癌患者的总体存活率仍然很低(5)。 这种低存活率可能是由于确诊时疾病处于相对晚期所致。如果肺 癌症可以在进展到晚期之前的癌前阶段被识别和阻止，我们 可以提高患者的存活率。然而，人们对区分创业障碍症的生物标志物知之甚少。 来自正常组织和驱动创业症启动和进展的分子。最近的证据表明 研究表明，肿瘤内细胞的异质性有助于肿瘤的发生和发展，包括 肺癌(6例)。肿瘤起始细胞(TIC)或癌症干细胞是大部分肿瘤细胞的一个亚群。 这可以概括整个肿瘤的异质结构，并在功能上推动肿瘤的形成。核子 核因子-κB(NF-κB)是炎症反应的关键介质，最近被认为与 抽搐的司机(7)。最近，人们发现炎症可以改变某些基因的表达。 MicroRNAs(MiRNAs)，包括致癌miR-21(8)的上调。MiRNAs是非编码RNA 属于一类通过与互补基因结合来控制基因表达的新型调控分子 同时在多个靶信使RNA(MRNA)转录本上的位点(9)。然而，信号事件 将癌症干细胞相关的miRNA与炎症性病变的启动和进展联系起来 微环境尚待绘制。我们假设炎症导致miRNA在 痉挛可能在KRASmut或表皮生长因子受体中驱动癌前病变的启动和进展 (EGFRmut)肺腺癌患者，深入了解这一点可能会发现新的靶点 用于基于miRNA的治疗。在目标1中，我们将描述肺内创业增生症的miRNA特征。 纸巾。在目标2中，我们将研究miRNA抑制剂或模拟物在防止糖尿病进展中的作用。 肺癌由癌变到瘤变。在这些研究的结论中，我们将产生一种新的肿瘤 有机类模型，开发出用于治疗癌前病变和预防恶性病变的miRNA疗法 进展，以及获得关于抽搐和炎性利基的作用的创新信息 在创业期的启动和发展。

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.