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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA180779-02
Application #
8755900
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2018) Biomarkers and immunoprofiles associated with fetal abnormalities of ZIKV-positive pregnancies. JCI Insight 3:
Zhang, Junjie; Zhao, Jun; Xu, Simin et al. (2018) Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication. Cell Host Microbe 24:234-248.e5
Liang, Qiming; Wei, Dahai; Chung, Brian et al. (2018) Novel Role of vBcl2 in the Virion Assembly of Kaposi's Sarcoma-Associated Herpesvirus. J Virol 92:
Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2017) Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy. Nat Microbiol 2:1558-1570
Yuan, Hongfeng; Tan, Brandon; Gao, Shou-Jiang (2017) Tenovin-6 impairs autophagy by inhibiting autophagic flux. Cell Death Dis 8:e2608
Hwang, Sung-Woo; Kim, DongIk; Jung, Jae U et al. (2017) KSHV-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits interferon alpha production. Biochem Biophys Res Commun 486:700-705
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
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:
Cheng, Fan; He, Meilan; Jung, Jae U et al. (2016) Suppression of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by 5'-AMP-Activated Protein Kinase. J Virol 90:6515-6525
Li, Wan; Yan, Qin; Ding, Xiangya et al. (2016) The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA. PLoS Pathog 12:e1005605

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