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Systematic dissection of function and mechanism of long non-coding RNAs in glioblastoma

系统解析长非编码RNA在胶质母细胞瘤中的功能和机制

基本信息

批准号：
10390363
负责人：
Yiwen Chen
金额：
$ 40.5万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390363
关键词：
Adult Binding Biological Assay Biology Brain CCND1 gene CCNE2 gene CRISPR interference Cell Cycle Cell Cycle Progression Cell Proliferation Cells Clinical Sciences Code DNA Double Strand Break DNA Repair Data Development Diagnostic Diffuse Disease Dissection Double Strand Break Repair E2F transcription factors FOXM1 gene G1/S Transition Genes Genetic Transcription Genomics Glioblastoma Glioma Gliomagenesis Goals Human In Vitro Infiltration Ionizing radiation Maintenance Malignant - descriptor Mass Spectrum Analysis Mediating Messenger RNA Molecular Neuroglia Nucleotides Pathogenesis Patients Post-Transcriptional Regulation Primary Brain Neoplasms Prognostic Marker Proteins Proteomics RNA RNA-Binding Proteins Radiation Tolerance Radiation therapy Regulation Research Resistance Role Spinal Cord Neoplasms Stress Therapeutic Untranslated RNA Xenograft Model base brain tissue cell growth clinical prognosis crosslinking and immunoprecipitation sequencing effective therapy gain of function homologous recombination in vivo insight loss of function multiple omics novel novel therapeutic intervention protein complex public health relevance ribosome profiling self-renewal standard care stem cell proliferation stem cell self renewal stem cells therapeutically effective transcription factor transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM), a high-grade glioma (grade IV), is the most prevalent and malignant primary brain tumor in adults. There is no effective treatment of GBM. After standard treatment, the median survival of GBM patients is around 15 months. GBM is featured by enhanced cell proliferation, high propensity of invasion/diffuse infiltration throughout the brain, and resistance to chemo-/radiation therapy. Emerging evidence supports that long non-coding RNAs (lncRNAs, ~18,000 human lncRNA genes) can mediate tumor- promoting/suppressing effects and serve as independent diagnostic/prognostic biomarkers. Our previous integrative genomic study revealed that many lncRNAs show dysregulated expression, are associated with clinical prognosis, or harbor frequent somatic copy number alterations in GBM, suggesting an important role of lncRNAs in GBM pathogenesis. However, the function and mechanism of most lncRNAs in GBM are unknown. To fill this gap, our long-term goal is to leverage systematic multi-omic approaches to characterize the function and mechanism of lncRNAs in GBM, and to help develop new therapeutic strategies based on novel insight into lncRNA regulation in GBM. Our large-scale loss-of-function screen using CRISPR interference (CRISPRi) identified an antisense lncRNA, lnc-YINC (YBX1-interacting lncRNA) that was critical for GBM cell growth and was significantly up-regulated in GBM compared with normal brain tissue and low-grade glioma (LGG). The higher expression of lnc-YINC was associated with shorter overall survival of GBM patients. Functionally, lnc- YINC acted in-trans and was a key regulator of cell cycle progression of GBM cells/glioma stem cells (GSCs) and self-renewal of GSCs. It also protected GBM cells/GSCs from DNA double-strand breaks (DSBs) caused by endogenous stress or exogenous ionizing radiation. Mechanistically, lnc-YINC interacted with YBX1, and post-transcriptionally regulated the expression of key regulators of cell cycle or DSB repair, at least partially by stabilizing their mRNAs. Based on these new findings, we hypothesize that lnc-YINC is a GBM-promoting lncRNA that promotes proliferation of and modulates radio-sensitivity of GBM cells/GSCs, by enhancing YBX1 binding to key regulators of cell cycle/DSB repair and co-regulating their expression at post-transcriptional level. The objectives of this proposal are (a) to determine the role of lnc-YINC in gliomagenesis, (b) to integrate enhanced CLIP-seq (eCLIP-seq), ribosome profiling, RNA-seq and quantitative mass spectrometry data, with functional assays to identify the downstream targets of lnc-YINC/YBX1 that are key to regulating cell cycle or DSB repair, (c) to dissect the molecular mechanisms whereby lnc-YINC/YBX1 axis post-transcriptionally regulates the expression of key regulators of cell cycle or DSB repair, (d) to determine the role of lnc-YINC in modulating radio-sensitivity of GBM cells/GSCs and to investigate the therapeutic impact of combining inhibition of lnc-YINC with radiation therapy on GBM maintenance in vivo. This application is strengthened by a team of experts of basic/clinical science of GBM, DNA damage repair, RNA biology and proteomics.

项目总结/文摘