RPMS1 circular RNAs in EBV malignancies

摘要 EBV是一种人类肿瘤病毒，是霍奇金淋巴瘤、非霍奇金淋巴瘤、 胃癌和鼻咽癌，并与淋巴瘤发病率的增加有关 在艾滋病毒感染患者的情况下。EB病毒通过一种或多种基因的表达促进肿瘤进展 更多的病毒基因在导致癌症的不同阶段激活致癌途径。一个 疱疹病毒的独特之处在于它们利用无病毒的“潜伏期”基因表达程序 复制发生时，只有一小部分病毒基因被表达，从而改变宿主细胞环境 以便于病毒的维护和持久性。其中一些途径被潜伏期基因改变 与肿瘤发生所需的途径改变重叠，EBV潜伏基因是导致 肿瘤表型。 由于非编码RNA不会引发适应性免疫反应，因此病毒非编码RNA在 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 通行证。我们已经发现，EBV表达一类主要非编码的RNA，称为环状 RNA(CircRNAs)。其中一些CircRNA在重新激活期间或在不同的潜伏期内唯一表达 它们可能在EBV感染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、潜伏期类型、再激活中的表达 样本，我们已经确定了一小部分EBV CircRNA，它们可能在EBV生物学中发挥基础作用 EB病毒相关癌症。通过对EB病毒的种间亲缘关系进行环状RNA组分析，恒河猴 淋巴病毒，我们发现其中两个在进化上是保守的，表明进化上对 维持它们的功能。在这个应用中，我们将分析普遍表达和保守的EBV CircRNA，CircRPMS1_E4_E3a。我们的初步研究表明，抑制CircRPMS1_E4_E3a会导致 抑制细胞增殖，表明促进细胞生长的基本表型。在这项提案中，我们 提出三个完整的目标来评估CircRPMS1_E4_E3a的基本机制 与染色质的相互作用和基因表达的调节(目标1)，这些相互作用对 调节细胞信号(AIM 2)，以及其细胞信号反应和细胞生长控制之间的联系(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).