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
Nicol, Samantha M; Sabbah, Shereen; Brulois, Kevin F et al. (2016) Primary B Lymphocytes Infected with Kaposi's Sarcoma-Associated Herpesvirus Can Be Expanded In Vitro and Are Recognized by LANA-Specific CD4+ T Cells. J Virol 90:3849-59
Li, Wan; Jia, Xuemei; Shen, Chenyou et al. (2016) A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway. Oncotarget 7:32286-305
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 90:6515-25
Lee, Hye-Ra; Mitra, Jaba; Lee, Stacy et al. (2016) Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Perturbs the G1-S Cell Cycle Progression via Deregulation of the cyclin D1 Gene. J Virol 90:1139-43
Zhang, Junjie; Feng, Hao; Xu, Simin et al. (2016) Hijacking GPCRs by viral pathogens and tumor. Biochem Pharmacol 114:69-81
Lee, Myung-Shin; Yuan, Hongfeng; Jeon, Hyungtaek et al. (2016) Human Mesenchymal Stem Cells of Diverse Origins Support Persistent Infection with Kaposi's Sarcoma-Associated Herpesvirus and Manifest Distinct Angiogenic, Invasive, and Transforming Phenotypes. MBio 7:e02109-15
Zhao, Jun; Li, Junhua; Xu, Simin et al. (2016) Emerging Roles of Protein Deamidation in Innate Immune Signaling. J Virol 90:4262-8
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
Liang, Qiming; Luo, Zhifei; Zeng, Jianxiong et al. (2016) Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy. Cell Stem Cell 19:663-671
Zhu, Ying; Ramos da Silva, Suzane; He, Meilan et al. (2016) An Oncogenic Virus Promotes Cell Survival and Cellular Transformation by Suppressing Glycolysis. PLoS Pathog 12:e1005648

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