KSHV microRNAs in cellular transformation and tumorigenesis

KSHV microRNA 在细胞转化和肿瘤发生中的作用

• 批准号: 8728172
• 负责人: Shou-Jiang Gao
• 金额: $ 19.46万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728172
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Blood Vessels; California; Cell Proliferation; Cell Survival; Cell model; Cells; China; Contact Inhibition; Development; Disease; Embryo; Genes; Genetic; Genome; Goals; HIV Infections; Herpesviridae Infections; Human; Human Herpesvirus 8; Individual; Kaposi Sarcoma; Knowledge; Laboratories; Malignant Neoplasms; Measures; Mediating; Medical; Mesenchymal; Mesenchymal Stem Cells; MicroRNAs; Modeling; Morbidity - disease rate; Multicentric Angiofollicular Lymphoid Hyperplasia; Nude Mice; Pathogenesis; Pathway interactions; Patients; Prevention; Prevention therapy; Proteins; Rattus; Role; Side; Societies; Testing; Therapeutic; Time; Universities; Viral; Virus; Virus Diseases; Virus Latency; Work; angiogenesis; base; cell growth; effective intervention; expectation; innovation; insight; metaplastic cell transformation; mortality; mutant; neoplastic cell; novel; positional cloning; precursor cell; primary effusion lymphoma; prognostic; public health relevance; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), a vascular cancer commonly found in AIDS patients. Despite extensive studies, the mechanism of KSHV-induced cellular transformation and tumorigenesis remains undefined. This critical gap of knowledge has impeded the development of effective intervention measures. We have shown that KSHV can efficiently infect and transform primary rat embryonic metanephric mesenchymal precursor cells (MM). KSHV-infected MM (KMM) induce KS-like tumors in nude mice. Using reverse genetics, we have found that a cluster of 10 KSHV pre-microRNAs (pre-miRs) is required for KSHV-induced cellular transformation and tumorigenesis. Encouraged by these findings, we have recently made significant progresses in infecting and transforming human primary cells with KSHV. Specifically, we have found that KSHV can also infect, immortalize and transform human primary mesenchymal stem cells (MSC), the human version of MM. This collaborative application between the University of Southern California and Nanjing Medical University proposes to extend these exciting paradigm-shifting discoveries with the objective to refine the MSC model, and use both the MM and MSC models to identify the specific miRs that mediate KSHV cellular transformation and tumorigenesis, and define the essential cellular genes and pathways that are targeted by these miRs. Based on our preliminary results, we have formulated a working hypothesis that KSHV can infect and transform MSC, and specific KSHV miRs manipulate essential cell growth and survival pathways, contributing critically to KSHV-induced cellular transformation and tumorigenesis. Therefore, the proposed project will refine the model of KSHV cellular transformation of human primary MSC (Aim 1); determine the contribution of individual viral pre-miRs and miRs to KSHV-induced cellular transformation and tumorigenesis by genetic complementation (Aim 2); determine the effect of individual viral pre-miRs and miRs on cellular transformation, and identify those that regulate cell growth, survival, angiogenesis and invasion (Aim 3); and delineate the mechanism of viral miRs- mediated KSHV-induced cellular transformation and tumorigenesis by identifying the essential direct targets (Aim 4). This collaborative project takes advantage of the expertise of the US and China laboratories. These works are significant and innovative because they will, for the first time, show that KSHV can truly transform human primary cells, define the functions and mechanisms of action of KSHV miRs in cellular transformation and tumorigenesis, and identify potential novel targets for developing innovative prognostic and therapeutic approaches. The study will also establish a novel paradigm of oncogenesis mediated by viral subversion of the miR pathway, thus providing insights into the oncogenesis of other cancers.

描述(申请人提供)：卡波西肉瘤相关疱疹病毒(KSHV)是卡波西肉瘤(KS)的病原体，KS是一种常见于艾滋病患者的血管癌。尽管有广泛的研究，但KSHV诱导细胞转化和肿瘤发生的机制仍不清楚。这一严重的知识差距阻碍了制定有效的干预措施。我们发现KSHV能有效地感染和转化原代大鼠胚胎后肾间充质前体细胞。KSHV感染的MM(KMM)在裸鼠体内诱发KS样瘤。利用反向遗传学，我们发现KSHV诱导的细胞转化和肿瘤发生需要10个KSHV前microRNAs(pre-miRs)。在这些发现的鼓舞下，我们最近在用KSHV感染和转化人类原代细胞方面取得了重大进展。具体地说，我们发现KSHV还可以感染、永生化和转化人类原代间充质干细胞(MSC)，即人类版本的MM。这项南加州大学和南京医科大学的合作应用提议扩展这些令人兴奋的范式转换发现，以完善MSC模型，并使用MM和MSC模型来确定介导KSHV细胞转化和肿瘤发生的特定MIR，并定义这些MIR所针对的基本细胞基因和途径。根据我们的初步结果，我们提出了一个工作假说，即KSHV可以感染和转化MSC，并且特定的KSHV miRs调控重要的细胞生长和生存途径，在KSHV诱导的细胞转化和肿瘤发生中起关键作用。因此，拟议的项目将完善KSHV对人原代MSC的细胞转化模型(目标1)；确定单个病毒前miR和miR通过遗传互补在KSHV诱导的细胞转化和肿瘤形成中的作用(目标2)；确定单个病毒前miR和miR对细胞转化的影响，并确定调控细胞生长、存活、血管生成和侵袭的那些(目标3)；通过确定基本的直接靶点来描述病毒miRs介导的KSHV诱导的细胞转化和肿瘤形成的机制(目标4)。这个合作项目利用了美国和中国实验室的专业知识。这些工作具有重大意义和创新性，因为它们将首次表明KSHV可以真正转化人类原代细胞，确定KSHV miRs在细胞转化和肿瘤发生中的功能和作用机制，并确定潜在的新靶点，以开发创新的预后和治疗方法。这项研究还将建立一个由病毒颠覆miR途径介导的肿瘤发生的新范式，从而为其他癌症的肿瘤发生提供见解。