Regulation of the Tumor Microenvironment by KSHV

KSHV 对肿瘤微环境的调节

• 批准号: 8403765
• 负责人: Christopher H Parsons
• 金额: $ 27.24万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403765
• 关键词: AIDS/HIV problem; Address; Amino Acids; Binding; Blood Circulation; Cell Culture System; Cell Death; Cell Line; Cell Survival; Cells; Clinic; Clinical; Clinical Data; Clinical Research; Common Neoplasm; Data; Endothelial Cells; Environment; Exhibits; Future; Gene Transfer; Generations; Genetic Transcription; Glutathione; HIV; HIV Infections; Herpesviridae Infections; Human; Human Herpesvirus 8; Immunosuppression; In Vitro; Infection; Kaposi Sarcoma; Lesion; Link; Longevity; Malignant Neoplasms; Membrane; Membrane Transport Proteins; MicroRNAs; Mononuclear; Morbidity - disease rate; Mus; Nitric Oxide Synthase; Oral cavity; Oxidative Stress; Pathogenesis; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Play; Prevention; Preventive; Production; Protein Subunits; Proteins; Reactive Nitrogen Species; Regulation; Regulatory Pathway; Relative (related person); Risk; Role; Sampling; Science; Serum; Source; Stress; Toxic effect; Up-Regulation; Virus Receptors; autocrine; base; cell type; design; extracellular; functional outcomes; gammaherpesvirus; macrophage; men who have sex with men; monocyte; mortality; novel; novel therapeutics; paracrine; peripheral blood; permissiveness; promoter; public health relevance; receptor; research study; skin lesion; therapeutic target; treatment strategy; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS) remains the most common tumor arising in patients with HIV/AIDS, and involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. Kaposi's sarcoma-associated herpesvirus (KSHV) replication and ongoing infection of target cells plays an important role in KS pathogenesis. An amino acid membrane transport protein subunit, xCT, maintains intracellular glutathione stores to enhance the survival of cells producing reactive nitrogen species (RNS), and xCT was recently identified as a fusion-entry receptor for KSHV (Kaleeba and Berger, Science, 2006). A number of intracellular and extracellular triggers regulate xCT expression, including binding of the xCT promoter by transcription regulators and the activation of positive transcription regulators by RNS. We have determined recently that xCT is expressed by multiple cell types within KS lesions and circulating mononuclear cells from HIV-infected patients, with cells from KSHV/HIV co-infected patients exhibiting the highest xCT expression. However, it is unknown whether KSHV itself regulates xCT expression to promote KSHV infection and persistence in the local environment. KSHV infects macrophages within KS lesions, and macrophages are a principal source of RNS. Using a novel macrophage cell culture system, our preliminary data suggest that KSHV microRNA suppress BACH-1, a negative transcription regulator of xCT expression, and that KSHV induces RNS secretion by macrophages. Based on these preliminary data, we hypothesize that KSHV promotes its own persistence in the local environment by upregulating xCT expression through both paracrine and autocrine mechanisms, and that targeting xCT regulatory pathways reduces KSHV infection and persistence in the microenvironment. To address this hypothesis, we propose two independent aims: 1) to determine mechanisms and functional outcomes for xCT regulation by KSHV; and 2) to determine clinical relationships between KSHV infection, xCT expression and RNS production in HIV-infected patients at greatest risk for KS. Through these efforts, we hope to provide the framework for developing novel therapeutic strategies for KS through the targeting of xCT and the reduction of KSHV infection and persistence within the tumor microenvironment.

描述（由申请人提供）：卡波西肉瘤（KS）仍然是HIV/AIDS患者中最常见的肿瘤，口腔受累是该肿瘤最常见的临床表现之一。卡波西肉瘤相关疱疹病毒（KSHV）的复制和持续感染的靶细胞在KS发病机制中起着重要作用。氨基酸膜转运蛋白亚基xCT维持细胞内谷胱甘肽储存以增强产生活性氮物质（RNS）的细胞的存活，并且xCT最近被鉴定为KSHV的融合进入受体（Kaleeba和Berger，Science，2006）。许多细胞内和细胞外触发因子调节xCT表达，包括转录调节因子与xCT启动子的结合以及RNS对正转录调节因子的激活。我们最近已经确定，xCT由KS病变内的多种细胞类型和来自HIV感染患者的循环单核细胞表达，来自KSHV/HIV共感染患者的细胞表现出最高的xCT表达。然而，尚不清楚KSHV本身是否调节xCT表达以促进KSHV感染并在局部环境中持续存在。KSHV感染KS病变内的巨噬细胞，巨噬细胞是RNS的主要来源。使用一种新的巨噬细胞培养系统，我们的初步数据表明，KSHV microRNA抑制BACH-1，一种xCT表达的负转录调节因子，KSHV诱导巨噬细胞分泌RNS。基于这些初步数据，我们假设KSHV通过旁分泌和自分泌机制上调xCT表达来促进其自身在局部环境中的持久性，并且靶向xCT调节途径减少了KSHV感染和在微环境中的持久性。为了解决这一假设，我们提出了两个独立的目标：1）确定KSHV调节xCT的机制和功能结局; 2）确定KS风险最高的HIV感染患者中KSHV感染、xCT表达和RNS产生之间的临床关系。通过这些努力，我们希望通过靶向xCT和减少KSHV感染和在肿瘤微环境中的持久性，为开发KS的新治疗策略提供框架。