ROLE OF Rac AND REACTIVE OXYGEN SPECIES IN KAPOSI'S SARCOMA VIRAL ONCOGENESIS

Rac 和活性氧在卡波西肉瘤病毒癌发生中的作用

• 批准号: 8447382
• 负责人: Pascal J. Goldschmidt-Clermont
• 金额: $ 39.59万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447382
• 关键词: Acetylcysteine; Acquired Immunodeficiency Syndrome; Affect; Animal Disease Models; Animal Model; Anti-Retroviral Agents; Antioxidants; Biopsy; Blood; Cell Proliferation; Cells; Chemopreventive Agent; Collaborations; Comprehensive Cancer Center; Data; Development; Down-Regulation; Drug Targeting; Endothelial Cells; FDA approved; Family; Gastrointestinal tract structure; Gender; Gene Expression; Gene Expression Profile; Genes; Genetic; Guanosine Triphosphate Phosphohydrolases; Highly Active Antiretroviral Therapy; Human Herpesvirus 8; Human Identifications; In Vitro; Kaposi Sarcoma; Laboratories; Lead; Lesion; Ligands; Link; Local Therapy; Lung; Malignant Neoplasms; Mediator of activation protein; Modeling; Morbidity - disease rate; Mucous Membrane; Multifocal Lesion; Mus; Mutation; NADPH Oxidase; Names; Oxidative Stress; Pathogenesis; Patients; Pharmaceutical Preparations; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Prevention; Production; Reactive Oxygen Species; Role; Signal Transduction; Skin; Smooth Muscle Actin Staining Method; Testing; Transgenic Mice; Universities; Up-Regulation; Vascular Endothelial Growth Factors; Viral; Viral Genes; Viscera; Work; angiogenesis; base; c-myc Genes; cancer type; carcinogenesis; cell transformation; chemotherapy; drinking water; efficacy testing; global health; in vivo; insight; latent gene expression; male; medical schools; member; mortality; mouse model; mutant; new therapeutic target; prevent; promoter; public health relevance; therapeutic target; therapy design; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS), caused by the Kaposi's sarcoma-associated herpes virus (KSHV), is a major cancer associated with AIDS and a global health challenge. The tumor is characterized by intense angiogenesis and the proliferation of spindle cells that can affect the skin, mucosa and viscera, causing significant morbidity. Understanding the role of viral and cellular genes leading to KS carcinogenesis is paramount to developing rationally designed therapies for KS. A collaboration between the Mesri and Goldschmidt labs has led to the identification of the Rac1 GTPase, a signaling mediator that triggers production of reactive oxygen species (ROS) by non-phagocytic NADPH-oxidase (NOX), as a potential major player in KS. We have found that expression of a constitutively-active Rac1 mutant (RacCA) driven by -smooth muscle actin (-SMA) promoter in transgenic mice led to the formation of lesions that strongly resemble those of Kaposi's sarcoma. Significantly, RacCA--SMA tumors revealed major transcriptome overlap with KS tumor biopsies. RacCA tumorigenesis was linked to male gender, and involved ROS activation of angiogenesis and cell proliferation. Furthermore, we found that AIDS-KS lesions and KSHV-infected tumors from our KS mouse model (mouse endothelial cell KSHV Bac36- mECK36) over-express Rac1 in all KSHV-infected (LANA+ve) cells. Moreover, we found that KS lesions and mECK36 lesions over-express key members of the NOX family and that mECK36 tumors upregulate NOX members in a KSHV dependent fashion. This led us to test the ability of N-acetyl cysteine (NAC), a well characterized antioxidant, to suppress mECK36 tumors in mice. We found that NAC prevented KSHV-induced tumor formation. Interestingly, we also found that NAC inibited VEGF, c-myc and viral gene expression in the mECK36 tumors through a mechanism involving platelet derived growth factor (PDGF) receptor and ligand downregulation. These data indicate that Rac1, NOX, ROS, and their downstream effectors are molecules actively involved in KS viral oncogenesis, and suggest that Rac1 signaling and oxidative stress could be attractive KS chemopreventive and therapeutic targets. We proposse to: Study mechanisms and role of Rac1 activation in KSHV oncogenesis (Aim 1), study the role of NADPH oxidase induction of ROS in KSHV oncogenesis (Aim 2) and to test the efficacy of pharmacologic ROS inhibition on prevention and treatment of RacCA and KSHV-induced tumors (Aim 3).

描述（由申请人提供）：Kaposi的肉瘤（KS）是由Kaposi与肉瘤相关的疱疹病毒（KSHV）引起的，是与AIDS和全球健康挑战有关的主要癌症。肿瘤的特征是强烈的血管生成和可能影响皮肤，粘膜和内脏的纺锤体细胞的增殖，从而导致明显的发病率。了解导致KS癌变的病毒和细胞基因的作用对于开发KS合理设计的疗法至关重要。 Mesri和Goldschmidt Labs之间的合作导致了Rac1 GTPase的鉴定，Rac1 GTPase是一种信号传导介质，可通过非磷酸细胞NADPH-氧化酶（NOX）触发活性氧（ROS）的产生，作为KS的潜在主要参与者。我们发现，由 - 平滑肌肌动蛋白（-sMA）启动子驱动的组成型Rac1突变体（RACCA）在转基因小鼠中的表达导致了与Kaposi肉瘤相似的病变的形成。值得注意的是，RACCA-SMA肿瘤揭示了与KS肿瘤活检的主要转录组重叠。 RACCA肿瘤发生与男性性别有关，涉及血管生成和细胞增殖的ROS激活。此外，我们发现所有KSHV感染的（LANA+VE）细胞中的KS小鼠模型（小鼠内皮细胞KSHV BAC36-MECK36）的AIDS-KS病变和KSHV感染的肿瘤过表达Rac1。此外，我们发现NOX家族的KS病变和Meck36病变过表达的主要成员，Meck36肿瘤以KSHV依赖性方式上调了NOX成员。这导致我们测试了一种表征良好的抗氧化剂N-乙酰基半胱氨酸（NAC）抑制小鼠Meck36肿瘤的能力。我们发现NAC阻止了KSHV诱导的肿瘤形成。有趣的是，我们还发现，NAC通过涉及血小板衍生的生长因子（PDGF）受体和配体下调的机制在MECK36肿瘤中捕获了VEGF，C-MYC和病毒基因表达。这些数据表明RAC1，NOX，ROS及其下游效应子是积极参与KS病毒肿瘤生成的分子，并表明Rac1信号传导和氧化应激可能是有吸引力的KS化学预防和治疗靶标。我们提出：RAC1激活在KSHV肿瘤发生中的研究机制和作用（AIM 1），研究NADPH氧化酶诱导ROS在KSHV肿瘤中的作用（AIM 2）以及测试药理学ROS ROS抑制在预防和治疗RACCA和KSHV诱导的肿瘤方面的功效（AIM AIM 3）。