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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：
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
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/10177973
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.

项目总结