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KSHV microRNAs in tumor invasion and angiogenesis

KSHV microRNA 在肿瘤侵袭和血管生成中的作用

基本信息

批准号：
9906178
负责人：
Shou-Jiang Gao
金额：
$ 18.97万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-03 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906178
关键词：
Acquired Immunodeficiency Syndrome Binding Cells China Clinical Trials Coupled Development Etiology Funding G protein coupled receptor kinase Genome Glutamic Acid Goals Herpesviridae Infections Highly Active Antiretroviral Therapy Human Human Herpesvirus 8 Individual Kaposi Sarcoma Laboratories Malignant - descriptor Malignant Neoplasms Mediating Mesenchymal Stem Cells MicroRNAs Modeling Molecular Morbidity - disease rate Multicentric Angiofollicular Lymphoid Hyperplasia Mutagenesis Mutate Organ Pathologic Pathway interactions Patients Phosphotransferases Prevention Proteins Proto-Oncogene Proteins c-akt Role SH3 Domains STAT3 gene Signal Transduction Site Societies Therapeutic Time Tumor Angiogenesis Tumor Cell Invasion Viral Visceral angiogenesis cellular targeting inhibitor/antagonist innovation insight mortality novel novel therapeutic intervention overexpression primary effusion lymphoma programs receptor therapeutic target tumor tumorigenesis

项目摘要

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several cancers. Despite highly active anti-retroviral therapy, Kaposi’s sarcoma (KS) remains as a dominant cancer in AIDS patients. The hallmark pathological features of KS are excessive deregulation of angiogenesis and extreme invasiveness manifested as multifocal tumors and involvement of visceral organs. Thus, understanding the molecular basis of KSHV-induced angiogenesis and cell invasion could serve as the basis for developing novel therapeutic approaches. Our US-China collaborative team funded by previous cycle of the US-China Program has made significant progresses toward this goal by 1) developing a novel model of KSHV infection of human primary mesenchymal stem cells (MSCs), in which KSHV induces angiogenesis, cell invasion, malignant transformation and tumorigenesis closely mimicking human KS tumors;; 2) demonstrating the essential roles of KSHV microRNAs (miRNAs) in KSHV-induced angiogenesis and cell invasion;; 3) identifying KSHV miR-K6-3p as a pro-angiogenic miRNA that induces angiogenesis by targeting SH3 domain-binding glutamic acid-rich protein (SH3BGR) to activate the STAT3 pathway;; and 4) demonstrating that KSHV miR-K3-5p promotes cell invasion by targeting G-protein coupled receptor kinase 2 (GRK2) to activate the AKT signaling. We propose to extend these exciting discoveries with the objective to further dissect the molecular mechanisms by which KSHV miRNAs promote tumorigenesis by inducing angiogenesis and cell invasion, and to explore the therapeutic application of these discoveries. The central hypothesis is that KSHV encodes specific miRNAs to activate angiogenic and invasive pathways contributing to KSHV-induced tumorigenesis, and as a result, targeting these pathways can effectively inhibit the development of KSHV-induced cancers. We will identify KSHV miRNAs that mediate KSHV-induced angiogenesis and define the mechanisms of action (Aim 1);; identify KSHV miRNAs that mediate KSHV-induced cell invasion and define the mechanisms of action (Aim 2);; delineate the roles of pro-angiogenic and pro-invasive miRNAs in the development of tumors, and in tumor angiogenesis and invasion (Aim 3);; and explore the therapeutic application of targeting angiogenic and invasive pathways activated by KSHV miRNAs in KSHV-induced tumorigenesis (Aim 4). This application will further reinforce the collaborative efforts of the two US and China teams with highly complementary expertise to accelerate the advancements of the proposed project that are otherwise difficult to achieve by the individual laboratories. The results from this project will be highly significant and innovative because they will, for the first time, define the functions and mechanisms of action of KSHV miRNAs in tumor angiogenesis and invasion in a genuine KS model, and identify novel targets for developing innovative therapeutic approaches. The study will also establish a novel paradigm of oncogenesis mediated by viral subversion of the miRNA pathway, thus providing insights into the oncogenesis of other cancers.

卡波西肉瘤相关疱疹病毒（KSHV）是几种癌症的病原体。尽管积极的抗逆转录病毒治疗，卡波西肉瘤（KS）仍然是艾滋病患者的主要癌症。 KS的标志性病理特征是过度的血管生成失调和极端的侵袭性表现为多灶性肿瘤并累及内脏器官。因此，了解其分子基础 KSHV-1诱导的血管生成和细胞侵袭可以作为开发新的治疗方法的基础。我们的美中合作团队由上一轮美中项目资助，通过1）开发KSHV感染人原发性肝癌的新模型，间充质干细胞（MSC），其中KSHV诱导血管生成，细胞侵袭，恶性转化和肿瘤发生密切模仿人类KS肿瘤; 102）证明的基本作用， KSHV microRNAs（miRNAs）在KSHV-miR-3 K6诱导的血管生成和细胞侵袭中的作用; 作为一种促血管生成的miRNA，通过靶向SH 3结构域结合富含谷氨酸的蛋白（SH 3BGR）激活STAT 3通路; 4）证明KSHV miR-PK 3-PK 5 p促进细胞增殖，通过靶向G-κ B蛋白偶联受体激酶2（GRK 2）激活AKT信号转导来抑制细胞侵袭。扩展这些令人兴奋的发现，目的是进一步剖析分子机制， KSHV miRNAs通过诱导血管生成和细胞侵袭促进肿瘤发生，并探讨其在肿瘤发生中的作用。这些发现的治疗应用。中心假设是KSHV编码特定的miRNAs，激活血管生成和侵袭途径，从而促进KSHV-HBV诱导的肿瘤发生，结果，靶向这些通路可以有效抑制KSHV-HBV诱导的癌症的发展。介导KSHV-1诱导的血管生成并定义作用机制的KSHV miRNAs（Aim 1）; 鉴定介导KSHV-1诱导的细胞侵袭的KSHV miRNAs，并确定其作用机制（目的2）; 描述了促血管生成和促侵袭性miRNA在肿瘤发生中的作用，血管生成和侵袭（Aim 3），探讨靶向血管生成和侵袭的治疗应用。在KSHV-miRNA诱导的肿瘤发生中由KSHV-miRNA激活的侵袭途径（目的4）。进一步加强中美两个具有高度互补专业知识的团队的合作努力加速推进个人难以实现的拟议项目该项目的结果将是非常重要的和创新的，因为它们将，首次明确了KSHV miRNAs在肿瘤血管生成和侵袭中的功能和作用机制在一个真正的KS模型，并确定新的目标，开发创新的治疗方法。还将建立一种新的由病毒破坏miRNA途径介导的肿瘤发生模式，为其他癌症的发生提供了新的见解。