An antisense RNA-mediated regulatory program that drives cancer metastasis

反义RNA介导的驱动癌症转移的调控程序

• 批准号: 10177973
• 负责人: Hani Goodarzi
• 金额: $ 42.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177973
• 关键词: 3' Untranslated Regions; Adjuvant Therapy; Antisense RNA; Binding; Bioinformatics; Biological Assay; Biology; Breast Cancer Cell; Breast Cancer Patient; Breast Epithelial Cells; Breast cancer metastasis; Cell physiology; Cells; Cellular Stress; Clinical; Computer Models; Data; Disease; Dissection; Enhancers; Enzymes; Equilibrium; Future; Gene Expression; Gene Expression Regulation; Genetic Transcription; Goals; Growth; High-Throughput Nucleotide Sequencing; Homeostasis; Longevity; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Metabolic; Metastatic breast cancer; Metastatic to; Methods; Molecular; NQO1 gene; Names; Neoplasm Metastasis; Normal Cell; Outcome; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathway interactions; Patients; Play; Poly A; Polyadenylation; Preparation; Process; Protein Isoforms; Proteins; Public Health; RNA; RNA Binding; RNA-Binding Proteins; Reactive Oxygen Species; Regulator Genes; Regulatory Pathway; Relapse; Research; Resistance; Role; Sampling; Shapes; Site; Stress; Technology; Testing; Transcript; Transfer RNA; Untranslated RNA; Up-Regulation; Xenograft Model; Xenograft procedure; base; cancer cell; clinically relevant; differential expression; experience; experimental study; human disease; in vivo; insight; mRNA Stability; malignant breast neoplasm; molecular phenotype; novel; overexpression; oxidative damage; programs; promoter; recruit; response; therapeutic target; transcription factor; transcriptome sequencing; tumor; tumor progression

PROJECT SUMMARY Post-transcriptional regulatory programs play a major role in shaping the aberrant gene expression landscape that is a hallmark of cancer progression. We have recently demonstrated that specific classes of non-coding RNAs, such as tRNAs (Goodarzi et al, Cell, 2016) and tRNA fragments (Goodarzi et al, Cell, 2015), play major roles in breast cancer metastasis as post-transcriptional regulators of gene expression. However, these regulatory RNAs are but a fraction of non-coding RNAs that are differentially expressed in highly metastatic cells. For example, antisense RNAs are a large but often ignored class of non-coding RNAs with poorly understood functions in the cell. We recently performed a systematic analysis of antisense RNAs expressed in a panel of poorly and highly metastatic breast cancer cells. We observed tens of antisense RNAs that are associated with metastatic capacity. Antisense RNAs can function as post-transcriptional regulators through their ability to form stable duplexes with their sense counterparts. However, the underlying molecular mechanisms and their role in gene expression regulation remains largely unknown. Here, we propose a detailed dissection of our top candidate antisense RNA, which targets the 3' UTR of the gene NQO1 and is hence named NQO1-AS, and its function in promoting breast cancer metastasis. We hypothesize that NQO1-AS forms a stable duplex with the 3' UTR of NQO1 which precludes the protein HNRNPC from binding. HNRNPC likely acts as a regulator of alternative poly(A) site selection in NQO1 mRNA, shifting the equilibrium towards an isoform with a truncated 3' UTR. We hypothesize that this truncated transcript isoform has a shorter life-span. Thus, by over-expressing NQO1-AS, highly metastatic cells post-transcriptionally increase the expression of NQO1. Enhanced NQO1 activity enables cancer cells to withstand the oxidative stress experienced during metastasis. In this study, we seek to perform a detailed dissection of this pathway, understand its role in metastasis, and test its clinical relevance in patients. Importantly, the enhanced NQO1 activity in highly metastatic cells can be exploited, using adjuvant therapies, to specifically target metastatic cells in patients with invasive breast cancer.

项目概要 转录后调控程序在塑造异常基因表达景观中发挥着重要作用 这是癌症进展的标志。我们最近证明了特定类别的非编码 RNA，例如 tRNA（Goodarzi 等人，Cell，2016）和 tRNA 片段（Goodarzi 等人，Cell，2015），发挥着主要作用。 作为基因表达的转录后调节因子在乳腺癌转移中的作用。然而，这些 调节RNA只是非编码RNA的一小部分，它们在高度转移的细胞中差异表达。 例如，反义 RNA 是一大类但经常被忽视的非编码 RNA，对其了解甚少。 在细胞中发挥作用。我们最近对一组表达的反义 RNA 进行了系统分析 低转移性和高转移性乳腺癌细胞。我们观察到数十种反义RNA 转移能力。反义 RNA 可以通过其形成转录后调节因子的能力发挥作用。 与它们的有义对应物形成稳定的双链体。然而，潜在的分子机制及其在其中的作用 基因表达调控仍然很大程度上未知。在这里，我们建议对我们的顶部进行详细剖析 候选反义RNA，其靶向基因NQO1的3'UTR，因此被命名为NQO1-AS，其 具有促进乳腺癌转移的作用。我们假设 NQO1-AS 与 NQO1 的 3' UTR，阻止蛋白质 HNRNPC 结合。 HNRNPC 可能充当监管机构 NQO1 mRNA 中的替代性 Poly(A) 位点选择，将平衡转向具有截短 3' 的异构体 UTR。我们假设这种截短的转录亚型的寿命较短。因此，通过过度表达 NQO1-AS，高度转移细胞转录后增加 NQO1 的表达。增强型NQO1 活性使癌细胞能够承受转移过程中经历的氧化应激。在这项研究中，我们 寻求对该通路进行详细剖析，了解其在转移中的作用，并测试其临床 与患者的相关性。重要的是，可以利用高度转移细胞中增强的 NQO1 活性，使用 辅助治疗，专门针对浸润性乳腺癌患者的转移细胞。