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

项目摘要 软组织肉瘤（STS）是一种罕见的间叶起源的肿瘤，通常以诊断为特征。 与肿瘤亚型相对应的融合癌蛋白。我们最近观察到，STS还具有 大量的非编码RNA（ncRNA）融合，其中RN7SK（7SK）融合是最突出的。 7SK ncRNA融合主要涉及其他RNA聚合酶III转录物，发生在特异性7SK 断裂点反映了已知的二级结构特征，并在原发性肿瘤中富集 而不是细胞系。此外，7SK融合体的存在与独特的基因表达相关， 信号，与肿瘤亚型无关。这种基因标记涉及转录因子的表达改变， 与转录调控、剪接和翻译相关的网络，7SK及其融合蛋白的已知功能 伙伴沿着预测的ncRNA融合体的二级结构，这表明潜在的 这些肿瘤中正常7SK调节功能的显著破坏。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组织中被破坏。 组织肉瘤，有助于疾病的发病机制。这个R03补助金的目的是让我们收集 基本的初步数据，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患病率。提出了两个具体目标： ·具体目标1：确定7SK融合体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融合的流行率 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，这项研究将为未来专注于了解ncRNA生物学的工作奠定基础。 肿瘤发生中的融合。

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.