Novel 7SK non-coding RNA fusions in soft tissue sarcomas to tumorigenesis

软组织肉瘤中新型 7SK 非编码 RNA 融合与肿瘤发生

• 批准号: 10201211
• 负责人: Joyce Ellen Ohm
• 金额: $ 8.41万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201211
• 关键词: Address; Biological Process; Biology; Cell Cycle; Cell Cycle Regulation; Cell Line; Cells; Characteristics; Chromosomal Rearrangement; Data; Diagnostic; Disease; Disease Progression; Elongation Factor; Engineering; Foundations; Fusion Oncogene Proteins; Future; Gene Expression; Gene Expression Profile; Genetic Transcription; Grant; Histologic; In Situ Hybridization; Knowledge; Link; Malignant Neoplasms; Manuscripts; Mesenchymal; Mesenchymal Cell Neoplasm; Molecular; Normal Cell; Normal tissue morphology; Oncogenic; Pathogenesis; Patients; Prevalence; Primary Neoplasm; Proteins; RNA; RNA Polymerase III; RNA Splicing; RNAse MRP; RNase P; Role; Sampling; Signal Transduction; Small Nuclear RNA; Small RNA; Soft tissue sarcoma; Structure; Tissue Microarray; Transcript; Transcriptional Regulation; Translations; Tumor Subtype; Tumor Tissue; Untranslated RNA; Work; base; cancer cell; cancer type; cohort; design; experimental study; fusion gene; genetic signature; malignant phenotype; novel; rare cancer; sarcoma; transcriptome sequencing; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin that are often characterized by diagnostic fusion oncoproteins corresponding with tumor subtype. We have recently observed that STS also harbor a significant number of non-coding RNA (ncRNA) fusions, with RN7SK (7SK) fusions being the most prominent. 7SK ncRNA fusions predominantly involve other RNA polymerase III transcripts, occur at specific 7SK breakpoints which reflect known characteristics of secondary structure, and are enriched in primary tumors over cell lines. Furthermore, the presence of 7SK fusions is associated with a unique gene expression signature, independent of tumor subtype. This gene signature involves altered expression of transcriptional networks linked to transcriptional regulation, splicing, and translation, known functions of 7SK and its fusion partners. Along with the predicted secondary structure of ncRNA fusions, this suggests the potential for significant disruption of normal 7SK regulatory function in these tumors. Our overall hypothesis is that 7SK ncRNA fusions represent a common mechanism by which normal transcription regulation is disrupted in soft tissue sarcomas, contributing to disease pathogenesis. This R03 grant has been designed to allow us to gather essential preliminary data to understand the biological function of these ncRNA in STS and query the prevalence of these ncRNA fusions in other tumor types. Two specific aims are proposed: • Specific Aim 1: To determine effects of 7SK fusions on gene expression and tumor growth • Specific Aim 2: To characterize the prevalence of ncRNA fusions in STS and normal mesenchymal cells and to extend these findings to other types of cancer and their normal counterparts If successful, this study will lay a foundation for future work focused on understanding the biology of ncRNA fusions in tumorigenesis.

项目概要 软组织肉瘤（STS）是间质来源的罕见肿瘤，其特征通常是诊断性的 与肿瘤亚型相对应的融合癌蛋白。我们最近观察到 STS 还包含一个 大量非编码 RNA (ncRNA) 融合，其中 RN7SK (7SK) 融合最为突出。 7SK ncRNA 融合主要涉及其他 RNA 聚合酶 III 转录本，发生在特定的 7SK 断点反映了已知的二级结构特征，并且在原发性肿瘤中丰富 超过细胞系。此外，7SK 融合体的存在与独特的基因表达有关 特征，与肿瘤亚型无关。该基因特征涉及转录表达的改变 与转录调控、剪接和翻译相关的网络、7SK 及其融合的已知功能 合作伙伴。连同预测的 ncRNA 融合二级结构一起，这表明了潜在的 这些肿瘤中正常的 7SK 调节功能受到显着破坏。我们的总体假设是 7SK ncRNA 融合代表了一种常见的机制，通过这种机制，正常的转录调控在软件中被破坏。 组织肉瘤，促进疾病发病机制。这笔 R03 赠款旨在让我们能够收集 重要的初步数据，以了解这些 ncRNA 在 STS 中的生物学功能并查询 这些 ncRNA 融合在其他肿瘤类型中的普遍性。提出了两个具体目标： • 具体目标 1：确定 7SK 融合对基因表达和肿瘤生长的影响 • 具体目标 2：表征 STS 和正常间充质细胞中 ncRNA 融合的普遍程度 细胞并将这些发现扩展到其他类型的癌症及其正常对应物 如果成功，这项研究将为未来重点了解 ncRNA 生物学的工作奠定基础 肿瘤发生过程中的融合。