Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with several AIDS-related cancers including Kaposi's sarcoma and primary effusion lymphoma. Despite intensive studies, the mechanisms underlying KSHV oncogenesis and persistent infection remain unclear. KSHV encodes more than two dozens microRNAs (miRs) derived from 12 precursor miRs. Others and we have shown that KSHV miRs regulate cell growth and survival, enhance cell invasion and angiogenesis, evade host immune responses, and promote viral latency. However, most of these studies have been carried out by overexpressing miRs without taking into consideration of KSHV infection. The objective of Project 3 is to identify the specific miRs and mechanisms that mediate KSHV oncogenesis and persistent infection in the context of viral infection. Our preliminary results have shown that a cluster of 10 KSHV pre-miRs is required for KSHV cellular transformation of primary mesenchymal stem cells (MSCs). Furthermore, we have shown that KSHV miR-K1 activates the NF- KB pathway and inhibits lytic replication by targeting IKBO while miR-KIO variants inhibit TGF-P pathway to block apoptosis by targeting TGF-(5 type II receptor. Therefore, our working hypothesis is that specific KSHV mlRs manipulate essential cellular pathways and key viral genes, contributing critically to KSHV oncogenesis and persistent infection. We have developed several novel systems that can address these challenges including model of KSHV cell growth transformation and tumorigenesis, model of KSHV infection in NOD/SCID lL2Ry-/- (NSG) "humanized" mice, KSHV reverse genetics system, and transcription activator-like effector nucleases (TALEN)-mediated genome editing technology. We will carry out the following three integrated and synergistic Specific Aims: 1. To identify KSHV essential miRs for cell growth transformation and tumorigenesis;2. To delineate the mechanisms by which KSHV miRs regulate oncogenesis;and 3. To identify KSHV essential miRs for persistent infection in NSG "humanized" mice. The proposed works are highly significant because they will, for the first time, define the functions and mechanisms of action of KSHV miRs in oncogenesis and persistent infection using innovative approaches and newly developed model systems. The study will establish a novel paradigm of oncogenesis mediated by viral subversion ofthe mlR pathway, thus providing insights into developing innovative therapeutic methods for KSHV-induced cancers and understanding the oncogenesis of other cancers.

Public Health Relevance

Kaposi's sarcoma is a common malignancy in AIDS patients in US 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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-J (M1))
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University of Southern California
Los Angeles
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Rodgers, Mary A; Bowman, James W; Fujita, Hiroaki et al. (2014) The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med 211:1333-47
Yan, Qin; Ma, Xinting; Shen, Chenyou et al. (2014) Inhibition of Kaposi's sarcoma-associated herpesvirus lytic replication by HIV-1 Nef and cellular microRNA hsa-miR-1258. J Virol 88:4987-5000
Brulois, Kevin; Toth, Zsolt; Wong, Lai-Yee et al. (2014) Kaposi's sarcoma-associated herpesvirus K3 and K5 ubiquitin E3 ligases have stage-specific immune evasion roles during lytic replication. J Virol 88:9335-49
Shi, Mude; Cho, Hyelim; Inn, Kyung-Soo et al. (2014) Negative regulation of NF-?B activity by brain-specific TRIpartite Motif protein 9. Nat Commun 5:4820
Zhu, Ying; Huang, Yufei; Jung, Jae U et al. (2014) Viral miRNA targeting of bicistronic and polycistronic transcripts. Curr Opin Virol 7:66-72
Brulois, Kevin; Jung, Jae U (2014) Interplay between Kaposi's sarcoma-associated herpesvirus and the innate immune system. Cytokine Growth Factor Rev 25:597-609
Jones, Tiffany; Ramos da Silva, Suzane; Bedolla, Roble et al. (2014) Viral cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition. Cell Cycle 13:845-58
Lee, Myung-Shin; Jones, Tiffany; Song, Dae-Yong et al. (2014) Exploitation of the complement system by oncogenic Kaposi's sarcoma-associated herpesvirus for cell survival and persistent infection. PLoS Pathog 10:e1004412
Full, Florian; Jungnickl, Doris; Reuter, Nina et al. (2014) Kaposi's sarcoma associated herpesvirus tegument protein ORF75 is essential for viral lytic replication and plays a critical role in the antagonization of ND10-instituted intrinsic immunity. PLoS Pathog 10:e1003863
Liang, Qiming; Seo, Gil Ju; Choi, Youn Jung et al. (2014) Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15:228-38

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