KSHV microRNAs in cellular transformation and tumorigenesis

KSHV microRNA 在细胞转化和肿瘤发生中的作用

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）的病原体，卡波西肉瘤是一种常见于艾滋病患者的血管癌。尽管进行了大量研究，但 KSHV 诱导的细胞转化和肿瘤发生的机制仍不清楚。这种严重的知识差距阻碍了有效干预措施的制定。我们已经证明KSHV可以有效地感染并转化原代大鼠胚胎后肾间充质前体细胞（MM）。 KSHV 感染的 MM (KMM) 在裸鼠中诱导 KS 样肿瘤。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一簇 10 个 KSHV pre-microRNA (pre-miR)。受这些发现的鼓舞，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。具体来说，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。南加州大学和南京医科大学之间的合作应用旨在扩展这些令人兴奋的范式转变发现，旨在完善 MSC 模型，并使用 MM 和 MSC 模型来识别介导 KSHV 细胞转化和肿瘤发生，并定义这些 miR 靶向的重要细胞基因和通路。根据我们的初步结果，我们提出了一个工作假设，即 KSHV 可以感染和转化 MSC，并且特定的 KSHV miR 操纵重要的细胞生长和生存途径，对 KSHV 诱导的细胞转化和肿瘤发生发挥关键作用。因此，拟议项目将完善人类原代MSC的KSHV细胞转化模型（目标1）；通过遗传互补确定个体病毒前 miR 和 miR 对 KSHV 诱导的细胞转化和肿瘤发生的贡献（目标 2）；确定单个病毒前 miR 和 miR 对细胞转化的影响，并确定那些调节细胞生长、存活、血管生成和侵袭的因子（目标 3）；并通过确定重要的直接靶标来描述病毒 miR 介导的 KSHV 诱导的细胞转化和肿瘤发生的机制（目标 4）。该合作项目利用了美国和中国实验室的专业知识。这些工作具有重要意义和创新性，因为它们将首次证明 KSHV 可以真正转化人类原代细胞，定义 KSHV miR 在细胞转化和肿瘤发生中的功能和作用机制，并确定开发创新预后的潜在新靶标。和治疗方法。该研究还将建立一种由病毒颠覆 miR 通路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。