Chimeric RNAs and their implication in lymphatic metastasis of bladder cancer

嵌合RNA及其在膀胱癌淋巴转移中的意义

• 批准号: 10582615
• 负责人: HUI LI
• 金额: $ 20.18万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582615
• 关键词: Address; Affect; Animal Model; Area; Basic Science; Biological Markers; Cancer Patient; Categories; Cause of Death; Cells; Cessation of life; Chemotherapy and/or radiation; Chimera organism; Chimeric Proteins; China; Chinese; Chromosomal Rearrangement; Clinical; Code; Collaborations; Collection; Country; DNA; Data; Databases; Deposition; Diagnostic; Disease; Disease Progression; FGFR3 gene; Fingerprint; Funding; Gender; Gene Fusion; Genes; Genomics; Genotype-Tissue Expression Project; Immunotherapy; Lymphatic; Lymphatic Metastasis; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Metastatic Neoplasm to Lymph Nodes; Modeling; Molecular; Multiomic Data; Neoplasm Metastasis; Neoplasms; Online Systems; Operative Surgical Procedures; Paper; Patients; Positive Lymph Node; Process; Prognosis; Prognostic Factor; Prognostic Marker; Proteins; Proteomics; Publishing; RNA; RNA Splicing; Recurrence; Reporting; Resources; Role; Sampling; Side; Somatic Mutation; TACC3 gene; The Cancer Genome Atlas; Therapeutic; Third Generation Sequencing; Trans-Splicing; Transcript; Untranslated RNA; Work; analysis pipeline; bioinformatics pipeline; cancer cell; cancer diagnosis; cancer type; chemotherapy; diagnostic biomarker; differential expression; driver mutation; epigenomics; epitranscriptomics; gene product; genome sequencing; improved; large datasets; lymph nodes; men; mortality; nanoparticle delivery; novel; novel diagnostics; novel therapeutic intervention; patient prognosis; sequencing platform; siRNA delivery; success; therapeutic target; transcriptome sequencing; transcriptomics; tumor; tumor progression; tumorigenic; whole genome

PROJECT SUMMARY Bladder cancer represents a common malignancy worldwide. The main cause of death in bladder cancer patients is metastasis, with lymphatic metastasis as the primary means. Metastatic bladder cancer is currently difficult to remove completely, and not sensitive to radiotherapy and chemotherapy. Better understanding and exploitation of new diagnostic and therapeutic strategy for lymphatic metastasis of bladder cancer is urgently needed. The study of gene fusions has founded the theoretical backgrounds for many cancer diagnosis and therapeutics. However, even with whole genome sequencing, novel recurrent gene fusions are rarely identified in bladder cancer. Recently, our work on RNA trans-splicing and intergenic cis-splicing have helped open a new paradigm for intergenic splicing processes that generate chimeric RNAs with pro-tumorigenic activities, and may explain the molecular basis of the presence of driver onco-fusion products in the absence of chromosomal rearrangement at the DNA level. Indeed, in our preliminary studies, we have identified several chimeric RNAs unique to bladder cancer, but produced by intergenic splicing. Within a month since the issue of the RFA, together with our Chinese collaborators, we have successfully identified a few chimeric RNAs that are differentially expressed in lymph node metastatic group using only partial data. This success plus our past fruitful collaboration encouraged us to propose the following aims: 1. To identify of chimeric RNAs associated with lymphatic metastasis of bladder cancer by combining the RNA-Sequencing data from TCGA and China. By integrating with CPTAC and whole genome sequencing data associated with TCGA, we can determine whether the chimeric RNAs may code for chimeric protein, and whether they are products of gene fusion or intergenic splicing. Using the clinical information from TCGA and Chinese patients, we will reveal the relationship between chimeric RNAs and lymphatic metastasis, disease progression, and prognosis; 2. To investigate the role of the chimeric RNAs in lymphatic metastasis of bladder cancer cells, and to elucidate the molecular mechanism of the chimeric RNAs in regulating lymphatic metastasis of bladder cancer; We will focus on two groups of chimeric RNAs, fusion protein-coding and long non-coding chimeric RNA (lnccRNA). 3. To explore the significance of chimeric RNA as an early diagnostic marker, prognostic factor, and therapeutic target for lymphatic metastasis of bladder cancer. We will investigate the potential of the candidate chimeric RNAs as biomarkers, and nanoparticle delivery of siRNAs to target key chimeric RNAs; and 4) To develop an interactive web-based database to disseminate the results. The proposed study fits the NCI Funding Priorities, Genomics/Epigenomics/Transcriptomics/Proteomics, in that we will combine the large multi-omics data from both countries, analyze the landscape of chimeric RNAs, and investigate their roles as protein-coding, or long non-coding in lymph node metastasis of bladder cancer. !

项目摘要 膀胱癌代表着全球常见的恶性肿瘤。膀胱癌死亡的主要原因 患者是转移，淋巴转移是主要手段。转移性膀胱癌目前正在 难以完全去除，并且对放疗和化学疗法不敏感。更好的理解和 对膀胱癌的淋巴转移的新诊断和治疗策略的开发是迫切的 需要。基因融合的研究建立了许多癌症诊断和 疗法。但是，即使进行了整个基因组测序，新型复发基因融合也很少被鉴定 在膀胱癌中。最近，我们在RNA跨式解体和基因间顺式切割方面的工作有助于开放 用于基因间剪接过程的新范式，该过程产生具有亲穆罗尼克活动的嵌合RNA， 并可以解释在没有驱动器融合产物的分子基础 DNA水平的染色体重排。确实，在我们的初步研究中，我们已经确定了几个 嵌合RNA是膀胱癌独有的，但由基因间剪接产生。自发行以来的一个月之内 RFA与我们的中国合作者一起，我们成功地确定了一些嵌合RNA 仅使用部分数据在淋巴结转移组中差异表达。这项成功加上我们的过去 富有成果的合作鼓励我们提出以下目标：1。确定相关的嵌合RNA 通过结合TCGA和中国的RNA测序数据，与膀胱癌的淋巴转移。 通过与与TCGA相关的CPTAC和整个基因组测序数据集成，我们可以确定 嵌合RNA是否可以编码嵌合蛋白，以及它们是基因融合的产物还是 基因间剪接。使用来自TCGA和中国患者的临床信息，我们将揭示 嵌合RNA与淋巴转移，疾病进展和预后之间的关系； 2 研究嵌合RNA在膀胱癌细胞淋巴转移中的作用，并阐明 嵌合RNA的分子机制在调节膀胱癌的淋巴转移中；我们将集中精力 在两组嵌合RNA上，融合蛋白编码和长的非编码嵌合RNA（LNCCRNA）。 3 探索嵌合RNA作为早期诊断标记，预后因素和治疗性的重要性 膀胱癌淋巴转移的靶标。我们将研究候选嵌合的潜力 RNA作为生物标志物，siRNA的纳米颗粒递送以靶向关键嵌合RNA； 4）开发一个 基于交互式Web的数据库来传播结果。拟议的研究符合NCI资金优先级， 基因组学/表观基因组学/转录组学/蛋白质组学，因为我们将从 两国，分析嵌合RNA的景观，并研究其作为蛋白质编码的作用，或者很长 膀胱癌的淋巴结转移中的非编码。 呢