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.

Public Health Relevance

Kaposi's sarcoma is a common malignancy in AIDS patients in US, China, and worldwide inflicting morbidity and mortality to the society. This project will investigate the mechanism underlining the development of Kaposi's sarcoma, and identify potential targets for the prevention and treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA177377-02
Application #
8728172
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2013-09-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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:
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
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
Qin, Jie; Li, Wan; Gao, Shou-Jiang et al. (2017) KSHV microRNAs: Tricks of the Devil. Trends Microbiol 25:648-661
Gruffaz, Marion; Vasan, Karthik; Tan, Brandon et al. (2017) TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway. Cancer Res 77:7094-7108
Zhu, Ying; Li, Tingting; Ramos da Silva, Suzane et al. (2017) A Critical Role of Glutamine and Asparagine ?-Nitrogen in Nucleotide Biosynthesis in Cancer Cells Hijacked by an Oncogenic Virus. MBio 8:

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