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

基本信息

批准号：
10435493
负责人：
Hani Goodarzi
金额：
$ 41.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/10435493
关键词：
3&apos 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

项目摘要

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.

项目摘要转录后调节计划在塑造异常基因表达格局中起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类 RNA，例如TRNA（Goodarzi等，Cell，2016）和TRNA片段（Goodarzi等，Cell，2015），发挥作用在乳腺癌转移中作为基因表达的转录后调节剂的作用。但是，这些调节性RNA只是在高度转移细胞中差异表达的非编码RNA的一部分。例如，反义RNA是一个很大但经常被忽略的非编码RNA类，知识较差细胞中的功能。我们最近对在一系列面板中表达的反义RNA进行了系统分析乳腺癌细胞不佳，高度转移性乳腺癌细胞。我们观察到数十个与之相关的反义RNA 转移能力。反义RNA可以通过其形成能力作为转录后调节剂发挥作用稳定的双工及其感官对应物。但是，基本的分子机制及其在基因表达调节在很大程度上仍然未知。在这里，我们提出了顶部的详细解剖候选反义RNA，靶向基因NQO1的3'UTR，因此被命名为NQO1-AS，它促进乳腺癌转移的功能。我们假设NQO1- AS与 3'NQO1的UTR，它排除了蛋白质HNRNPC的结合。 HNRNPC可能是 NQO1 mRNA中的替代聚（A）位点选择，将平衡转移到具有截短3'的同工型 UTR。我们假设这种截短的转录本相工相具有较短的寿命。因此，通过过表达 NQO1-AS，转交后高度转移性细胞增加了NQO1的表达。增强的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，我们寻求对该途径进行详细的解剖，了解其在转移中的作用，并测试其临床与患者相关。重要的是，可以利用高度转移细胞中增强的NQO1活性辅助疗法，以特异性靶向浸润性乳腺癌患者的转移细胞。