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 manifestedasmultifocaltumorsandinvolvementofvisceralorgans.Thus,understandingthemolecularbasis of KSHV-induced angiogenesis and cell invasion could serve as the basis for developing novel therapeutic approaches.OurUS-ChinacollaborativeteamfundedbypreviouscycleoftheUS-ChinaProgramhasmade 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 transformationandtumorigenesiscloselymimickinghumanKStumors;?2)demonstratingtheessentialrolesof KSHVmicroRNAs(miRNAs)inKSHV-inducedangiogenesisandcellinvasion;?3)identifyingKSHVmiR-K6-3p as a pro-angiogenic miRNA that induces angiogenesis by targeting SH3 domain-binding glutamic acid-rich protein(SH3BGR)toactivatetheSTAT3pathway;?and4)demonstratingthatKSHVmiR-K3-5ppromotescell invasionbytargetingG-proteincoupledreceptorkinase2(GRK2)toactivatetheAKTsignaling.Weproposeto 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 therapeuticapplicationofthesediscoveries.ThecentralhypothesisisthatKSHVencodesspecificmiRNAs 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);? identifyKSHVmiRNAsthatmediateKSHV-inducedcellinvasionanddefinethemechanismsofaction(Aim2);? 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 furtherreinforcethecollaborativeeffortsofthetwoUSandChinateamswithhighlycomplementaryexpertise toacceleratetheadvancementsoftheproposedprojectthatareotherwisedifficulttoachievebytheindividual laboratories.Theresultsfromthisprojectwillbehighlysignificantandinnovativebecausetheywill,forthe firsttime,definethefunctionsandmechanismsofactionofKSHVmiRNAsintumorangiogenesisandinvasion inagenuineKSmodel,andidentifynoveltargetsfordevelopinginnovativetherapeuticapproaches.Thestudy willalsoestablishanovelparadigmofoncogenesismediatedbyviralsubversionofthemiRNApathway,thus providinginsightsintotheoncogenesisofothercancers.
Kaposi?s sarcoma-associated herpesvirus (KSHV) causes several human cancers including Kaposi?s sarcoma, primary effusion lymphoma and multicentric Castleman?s disease. These malignancies inflict morbidity and mortality to the society in US and worldwide. This project will investigate the mechanisms underlining the development of these malignancies and KSHV infection, and identify therapeutic targets for developingnovelpreventionandtreatmentapproaches.
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