Kaposi's Sarcoma-associated Herpesvirus Mimics of Cellular microRNAs

卡波西肉瘤相关疱疹病毒的细胞 microRNA 模拟物

• 批准号: 8997993
• 负责人: Eva Henriette Gottwein
• 金额: $ 32.06万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997993
• 关键词: Acquired Immunodeficiency Syndrome; Actins; Address; Adherens Junction; Adhesions; Affect; B Cell Proliferation; B-Cell Lymphomas; B-Lymphocytes; Binding Sites; Biology; Blood Vessels; Cell Line; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Cellular Morphology; Code; Collaborations; Cytoskeleton; Data; Disease; Employee Strikes; Endothelial Cells; Gene Expression; Goals; Growth; Hallmark Cell; Health; Herpesviridae Infections; Human; Human Herpesvirus 8; Image; Individual; Infection; Inositol; Kaposi Sarcoma; Laboratories; Lentivirus Vector; Link; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Neoplasms; Oncogenic; PTEN gene; Pathogenesis; Phosphoric Monoester Hydrolases; Play; Property; Proteins; Publishing; Qualifying; Reagent; Regulation; Repression; Role; Sequence Homology; Signal Pathway; Signal Transduction; Staging; Structure; Testing; Untranslated RNA; Validation; Viral; Viral Oncogene; Virus; Work; angiogenesis; base; cell growth regulation; cell transformation; cellular targeting; infected B cell; mimicry; mutant; novel; primary effusion lymphoma; research study; response; transcriptome; tumorigenesis

DESCRIPTION: Kaposi's Sarcoma-associated herpesvirus (KSHV) causes the AIDS-associated malignancies Kaposi's Sarcoma (KS), and primary effusion lymphoma (PEL), resulting from KSHV-infection of endothelial cells (ECs) and B cells, respectively. KSHV encodes a set of microRNAs (miRNAs) with largely unknown significance to KSHV-associated disease. We have demonstrated that the KSHV miRNAs miR-K11, miR-K3 and miR-K10a repress mRNA targets of cellular miR-155, miR-23 and miR-142-3p, respectively. The goal of this proposal is to understand the potential significance of this mimicry to the pathogenesis of PEL and KS. Our preliminary data suggest that miR-K3 and miR-K11 together are essential for the survival of PEL-derived cell lines and synergize to target repressors of survival signaling and B-cell proliferation. In Aim 1, we therefore propose to phenotypically and mechanistically characterize the requirement for miR-K3 and miR-K11 for B-cell transformation by KSHV. Aims 2 and 3 address functions of miR-K10a. miR-K10a is expressed from the Kaposin A coding sequence, which has known oncogenic properties. Our preliminary experiments suggest that miR-K10a is the actual mediator of this transforming activity. In Aim 2, we therefore propose to further characterize the oncogenic properties of miR-K10a and to elucidate the underlying mechanism, based on already identified candidate targets with roles in transformation. Our analysis of miR-K10a targets and preliminary experiments suggest that miR-K10a functions in ECs to disrupt adherens junctions (AJs) and to remodel the actin cytoskeleton. miR-K10a expression caused a striking elongation of ECs, reminiscent of the KSHV-infected infected spindle cells that are the hallmark of KS. Because AJs and the linked actin cytoskeleton play important roles in vascular integrity, angiogenesis and the maintenance of EC quiescence by antagonizing growth factor signaling, their deregulation by miR-K10a may directly impact KS pathogenesis. In Aim 3, we therefore propose to phenotypically and mechanistically characterize how miR-K10a affects these structures and associated signaling pathways. Together, the proposed experiments will identify key roles of these KSHV miRNAs in KSHV oncogenesis.

描述：卡波西肉瘤相关疱疹病毒（KSHV）引起艾滋病相关的恶性肿瘤卡波西肉瘤（KS）和原发性积液性淋巴瘤（PEL），分别由KSHV感染内皮细胞（ECs）和B细胞引起。KSHV编码一组microrna (mirna)，其对KSHV相关疾病的意义在很大程度上未知。我们已经证明，KSHV miRNAs miR-K11、miR-K3和miR-K10a分别抑制细胞miR-155、miR-23和miR-142-3p的mRNA靶点。本提案的目的是了解这种拟态对PEL和KS发病机制的潜在意义。我们的初步数据表明，miR-K3和miR-K11共同对pel衍生细胞系的存活至关重要，并协同作用于生存信号和b细胞增殖的抑制因子。因此，在Aim 1中，我们提出对KSHV转化b细胞所需的miR-K3和miR-K11进行表型和机制表征。目的2和3涉及miR-K10a的功能。miR-K10a从已知的致癌特性的Kaposin A编码序列中表达。我们的初步实验表明，miR-K10a是这种转化活动的实际中介。因此，在Aim 2中，我们建议进一步表征miR-K10a的致癌特性，并基于已经确定的在转化中起作用的候选靶点来阐明潜在的机制。我们对miR-K10a靶点的分析和初步实验表明，miR-K10a在内皮细胞中起作用，破坏粘附连接（AJs）并重塑肌动蛋白细胞骨架。miR-K10a的表达引起了ECs的显著伸长，这让人想起了kshv感染的梭形细胞，这是KS的标志。由于AJs和相关的肌动蛋白细胞骨架通过拮抗生长因子信号在血管完整性、血管生成和EC静止维持中发挥重要作用，miR-K10a对它们的调节失调可能直接影响KS的发病机制。因此，在Aim 3中，我们建议对miR-K10a如何影响这些结构和相关信号通路进行表型和机制表征。总之，拟议的实验将确定这些KSHV mirna在KSHV肿瘤发生中的关键作用。