RPMS1 circular RNAs in EBV malignancies

总结 EBV是一种人肿瘤病毒，是霍奇金淋巴瘤、非霍奇金淋巴瘤、 胃癌和鼻咽癌，并与淋巴瘤的发病率增加有关 in the HIV病毒infected感染patient患者context上下文. EBV通过表达一种或多种靶基因， 更多的病毒基因，它们沿着导致癌症的阶段的进展激活致癌途径。一 疱疹病毒的一个独特方面是它们利用“潜伏”基因表达程序， 复制发生，并且只有一小部分病毒基因表达，其重塑宿主细胞环境 以促进病毒的维持和持久性。由于潜伏基因改变了某些途径 与肿瘤发生所需的途径改变重叠，EBV潜伏基因是肿瘤发生的关键因素。 肿瘤表型 因为非编码RNA不引起适应性免疫应答，所以在免疫应答中利用病毒非编码RNA是不可能的。 潜伏期设置是维持病毒在体内持续存在而不促进免疫的关键疱疹病毒策略 间隙我们已经发现EBV表达一类主要是非编码RNA，称为环状RNA， RNA（circRNA）。这些circRNA中的一些在再激活期间或在不同的潜伏期中独特地表达 它们可能在EBV感染级联的相应阶段发挥作用的类型。通过评估病毒 circRNA在体外和患者肿瘤中广泛的细胞类型、潜伏类型、再激活中的表达 在这些样本中，我们已经鉴定了一小部分EBV circRNA，它们可能在EBV生物学中发挥重要作用。 EBV相关癌症通过对EBV的种间亲属进行circRNAome分析， 淋巴隐病毒，我们发现其中两个是进化上保守的，表明进化上的限制， 保持其功能。在本申请中，我们将分析EB病毒的遍在表达和保守 circRNA，circRPMS1_E4_E3a。我们的初步研究表明，circRPMS1_E4_E3a的抑制导致 细胞增殖减少，表明促进细胞生长的基本表型。在本提案中，我们 提出了三个很好的综合目标，将评估circRPMS1_E4_E3a的基本机制 与染色质的相互作用和基因表达的调控（目的1），这些相互作用对 调节细胞信号（aim 2），以及其细胞信号应答与细胞生长控制（aim 3）。

Summary EBV is a human tumor virus that is an etiological agent in Hodgkin's lymphoma, non-Hodgkin's lymphomas, stomach cancer and nasopharygeal carcinoma, and it is associated with an increased incidence of lymphomas in the HIV-infected patient context. EBV contributes to oncogenic progression through the expression of one or more viral genes that activate oncogenic pathways along the progression of stages that lead to cancer. A unique aspect of herpesviruses is their utilization of “latency” gene expression programs where no virus replication occurs and only a small subset of viral genes is expressed that remodels the host cell environment to facilitate viral maintenance and persistence. With some of the pathways altered by latency genes overlapping with pathway alterations required for oncogenesis, EBV latency genes are key contributors to the tumor phenotype. Because non-coding RNAs do not elicit adaptive immune responses, the utilization of viral non-coding RNAs in latency settings is a key herpesviral strategy to sustain viral persistence in vivo without promoting immune clearance. We have discovered that EBV expresses a class of largely non-coding RNAs referred to as circular RNAs (circRNAs). Some of these circRNAs are expressed uniquely during reactivation or in distinct latency types where they likely play roles in the corresponding stages of the EBV infection cascade. By assessing viral circRNA expression across a broad range of cell types, latency types, reactivation, in vitro and in patient tumor samples, we have identified a small subset of EBV circRNAs that likely play fundamental roles in EBV biology EBV associated cancers. By performing a circRNAome analysis of the interspecies relative of EBV, the rhesus lymphocryptovirus, we found two of these to be evolutionarily conserved, indicating evolutionary constraints on maintaining their function. In this application, we will analyze the ubiquitiously expressed and conserved EBV circRNA, circRPMS1_E4_E3a. Our preliminary studies show that inhibition of circRPMS1_E4_E3a leads to decreased cell proliferation, indicating a fundamental phenotype in promoting cell growth. In this proposal, we propose three well integrated aims that will assess the fundamental mechanisms of circRPMS1_E4_E3a's interaction with chromatin and regulation of gene expression (aim 1), the influence of these interactions on modulating cell signaling (aim 2), and the link between its cell signaling responses and cell growth control (aim 3).