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. !

项目总结 膀胱癌是世界范围内常见的恶性肿瘤。膀胱癌的主要死亡原因 患者为转移，以淋巴转移为主要手段。转移性膀胱癌目前 难以完全切除，对放化疗不敏感。更好地了解和 开发膀胱癌淋巴转移新的诊断和治疗策略迫在眉睫 需要的。基因融合的研究为许多癌症的诊断和治疗奠定了理论基础 治疗学。然而，即使通过全基因组测序，也很少发现新的重复性基因融合。 得了膀胱癌。最近，我们在RNA反式剪接和基因间顺式剪接方面的工作帮助打开了一种 产生具有促肿瘤活性的嵌合RNA的基因间剪接过程的新范例， 并可以解释在缺乏DIVER的情况下存在共融合产物的分子基础 DNA水平上的染色体重排。事实上，在我们的初步研究中，我们已经确定了几个 膀胱癌特有的嵌合RNA，但由基因间剪接产生。在下发后一个月内 RFA与我们的中国合作者一起，成功地鉴定了几个嵌合RNA，它们是 仅使用部分数据在淋巴结转移组中差异表达。这一成功加上我们的过去 卓有成效的合作鼓励我们提出以下目标：1.识别相关的嵌合RNA 结合TCGA和中国的测序数据，对膀胱癌的淋巴转移进行研究。 通过结合CPTAC和与TCGA相关的全基因组测序数据，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。利用TCGA和中国患者的临床信息，我们将揭示 嵌合RNA与淋巴转移、疾病进展和预后的关系 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调控膀胱癌淋巴转移的分子机制 在两组嵌合RNA上，融合蛋白编码嵌合RNA和长非编码嵌合RNA(LnccRNA)。3.至 探讨嵌合RNA作为早期诊断标记物、预后因素和治疗的意义 膀胱癌淋巴转移的靶点。我们将调查候选嵌合体的潜力 RNA作为生物标记物，以及纳米颗粒传递siRNA以靶向关键的嵌合RNA；以及4)开发一种 以网络为基础的交互式数据库来传播结果。这项拟议的研究符合NCI资金优先事项， Genomics/Epigenomics/Transcriptomics/Proteomics，，因为我们将结合来自 这两个国家，分析了嵌合RNA的格局，并研究了它们作为蛋白质编码或Long的作用 非编码在膀胱癌淋巴转移中的作用 好了！