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 ...