Splicing factors and RNA processing alternations: exploring new players in glioblastoma development

剪接因子和 RNA 加工交替：探索胶质母细胞瘤发展中的新参与者

• 批准号: 9248321
• 负责人: Luiz Otavio Penalva
• 金额: $ 16.58万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248321
• 关键词: Affect; Alternative Splicing; Apoptosis; Biological; Biological Process; Cancer Etiology; Cell Line; Cell Survival; Cells; Characteristics; Chromosome abnormality; Clinical Trials; Collection; DNA Repair; Data Set; Defect; Development; Event; Frequencies; Gene Expression Regulation; Genes; Genomic Instability; Genomics; Glioblastoma; Glioma; Goals; Growth; Human; Incidence; Link; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Measures; Molecular; Mutation; Normal tissue morphology; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Process; Protein Isoforms; Protein Splicing; RNA Processing; RNA Splicing; RNA-Binding Proteins; Radio; Radioresistance; Recurrence; Regulation; Relapse; Resistance; Resources; Role; Route; Sampling; Source; Stem cells; Testing; The Cancer Genome Atlas; Transcript; Translating; Validation; Variant; Xenograft procedure; base; cancer type; clinically relevant; defined contribution; effective therapy; knock-down; migration; neoplastic cell; novel; outcome forecast; protein expression; protein function; public health relevance; response; temozolomide; tool; transcriptome; transcriptome sequencing; transcriptomics; translational impact; treatment response; tumor; tumor initiation; tumorigenesis

 DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is a highly malignant brain tumor type with 14 months average patient survival, high incidence of recurrence and no effective line of treatment. Genomic analyses became an essential resource to understand the molecular alterations that cause cancer. In the case of GBM, analysis of hundreds of samples produced an extensive transcriptomic map, identified prevalent mutations and defined important tumor drivers. Unfortunately, clinical trials based on these results have not yet delivered positiv outcomes. Therefore, we make a case for investigating other regulatory routes known to promote tumor relapse and influence treatment response. Our application focus on splicing, a critical regulatory step in which RNAs are assembled into mature transcripts. RNA binding proteins (RBPs) function as core regulators of the splicing process. We recently conducted a functional screen with all 1,542 human RBPs and identified SNRPB, ETFTUD2 and MAGOH as potential novel players in glioblastoma development. Specific Aims. In Aim 1, we propose to generate splicing profile maps for glioblastoma and link them to biological processes and pathways relevant to GBM development. In Aim 2, we will investigate the possible roles of SNRPB, ETFUD2 and MAGOH in tumor initiation, chemo- and radio-resistance and determine the splicing events/genes under their influence. In Aim 3, we will bridge datasets to establish a direct correlation between these 3 proteins and splicing alterations in GBM. Finally, the most relevant splicing events/genes derived from this analysis will be investigated to determine their role in cancer tumor initiation and therapy resistance.

 描述(申请人提供)：多形性胶质母细胞瘤(GBM)是一种高度恶性的脑肿瘤类型，患者平均存活14个月，复发率高，没有有效的治疗路线。基因组分析成为了解导致癌症的分子变化的重要资源。在GBM的案例中，对数百个样本的分析产生了广泛的转录图谱，识别了普遍存在的突变，并确定了重要的肿瘤驱动因素。不幸的是，基于这些结果的临床试验尚未产生积极的结果。因此，我们提出了研究其他已知的促进肿瘤复发和影响治疗反应的调控途径的案例。我们的应用重点是剪接，这是RNA组装成成熟转录本的关键调控步骤。RNA结合蛋白(RBPs)是剪接过程的核心调节因子。我们最近对所有1,542个人RBP进行了功能筛查，并确定SNRPB、ETFTUD2和MAGOH是胶质母细胞瘤发展中潜在的新成员。明确的目标。在目标1中，我们建议生成胶质母细胞瘤的剪接图谱，并将它们与与GBM发育相关的生物学过程和途径联系起来。在目标2中，我们将研究SNRPB、ETFUD2和MAGOH在肿瘤启动、化疗和放射耐药中的可能作用，并确定它们影响下的剪接事件/基因。在目标3中，我们将连接数据集，以建立这三种蛋白质与GBM剪接改变之间的直接关联。最后，从这一分析中获得的最相关的剪接事件/基因将被研究，以确定它们在癌症启动和治疗抵抗中的作用。

项目成果

The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes.

• DOI: 10.1080/15476286.2023.2221511
• 发表时间: 2023-01
• 期刊: RNA BIOLOGY
• 影响因子: 4.1
• 作者: Barreiro, Rodrigo A. S.;Guardia, Gabriela D. A.;Meliso, Fabiana M.;Lei, Xiufen;Li, Wei-Qing;Savio, Andre;Fellermeyer, Martin;Conceicao, Helena B.;Mercuri, Rafael L. V.;Landry, Tesha;Qiao, Mei;Blazquez, Lorea;Ule, Jernej;Penalva, Luiz O. F.;Galante, Pedro A. F.
• 通讯作者: Galante, Pedro A. F.

Functional genomics analyses of RNA-binding proteins reveal the splicing regulator SNRPB as an oncogenic candidate in glioblastoma.

• DOI: 10.1186/s13059-016-0990-4
• 发表时间: 2016-06-10
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Correa BR;de Araujo PR;Qiao M;Burns SC;Chen C;Schlegel R;Agarwal S;Galante PA;Penalva LO
• 通讯作者: Penalva LO