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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA213275-03
Application #
9735538
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2017-03-03
Project End
2022-02-28
Budget Start
2018-07-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Liu, Hui; Wang, Huaizhi; Wei, Zhen et al. (2018) MeT-DB V2.0: elucidating context-specific functions of N6-methyl-adenosine methyltranscriptome. Nucleic Acids Res 46:D281-D287
Yan, Qin; Zhao, Runran; Shen, Chenyou et al. (2018) Upregulation of MicroRNA 711 Mediates HIV-1 Vpr Promotion of Kaposi's Sarcoma-Associated Herpesvirus Latency and Induction of Pro-proliferation and Pro-survival Cytokines by Targeting the Notch/NF-?B-Signaling Axis. J Virol 92:
Tan, Brandon; Liu, Hui; Zhang, Songyao et al. (2018) Viral and cellular N6-methyladenosine and N6,2'-O-dimethyladenosine epitranscriptomes in the KSHV life cycle. Nat Microbiol 3:108-120
Gruffaz, Marion; Zhou, Shenghua; Vasan, Karthik et al. (2018) Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi's Sarcoma-Associated Herpesvirus Latent and Lytic Replications. MBio 9:
Cheng, Fan; Ramos da Silva, Suzane; Huang, I-Chueh et al. (2018) Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22. J Virol 92:
Jeon, Hyungtaek; Yoo, Seung-Min; Choi, Hyo Sun et al. (2017) Extracellular vesicles from KSHV-infected endothelial cells activate the complement system. Oncotarget 8:99841-99860
He, Meilan; Tan, Brandon; Vasan, Karthik et al. (2017) SIRT1 and AMPK pathways are essential for the proliferation and survival of primary effusion lymphoma cells. J Pathol 242:309-321
Yuan, Hongfeng; Tan, Brandon; Gao, Shou-Jiang (2017) Tenovin-6 impairs autophagy by inhibiting autophagic flux. Cell Death Dis 8:e2608
Li, W; Hu, M; Wang, C et al. (2017) A viral microRNA downregulates metastasis suppressor CD82 and induces cell invasion and angiogenesis by activating the c-Met signaling. Oncogene 36:5407-5420
Yuan, Hongfeng; He, Meilan; Cheng, Fan et al. (2017) Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy. Oncotarget 8:14912-14924

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