Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-miRNAs that are highly expressed in KS lesions and KSHV- associated lymphoproliferative malignancies. Ectopic expression and miRNA inhibition approaches, combined with gene expression profiling, have identified target mRNAs that are involved in the regulation of critical biological processes such as angiogenesis, apoptosis, endothelial cell differentiation, and immune surveillance. In addition, several miRNAs may regulate latency by targeting viral mRNAs. Preliminary analyses of the mRNAs targeted by KSHV miRNAs in PEL cells using HITS-CLIP technology to enrich RISC-associated RNAs have identified hundreds of new mRNA targets and confirmed previously identified targets. Moreover, our analysis showed that a high percentage of RISC complexes within PEL cells contain KSHV- encoded miRNAs. Based on these data, we hypothesize that the KSHV miRNAs cause significant and tissue-specific changes in gene expression that contribute to pathogenesis and tumorigenesis. To directly address this hypothesis we propose to 1) Comprehensively identify KSHV miRNA targets by HITS-CLIP in KSHV-infected PEL and endothelial cells;2) Characterize in vitro phenotypes and their associated regulatory pathways with respect to viral replication, the establishment and maintenance of latency, cell cycle control and resistance to apoptosis by using KSHV mutants lacking single or multiple miRNAs. In summary, combining ribonomics approaches for miRNA target identification with viral genetics, and the ability to determine viral phenotypes in cultured cells, will provide a detailed analysis of KSHV-encoded miRNA functions and may lead to the development of antiviral/antitumor strategies.
Human Herpesviruses cause many diseases including cancer and recently have been found to express miRNAs. Understanding how miRNA regulation of gene expression contributes to viral biology and pathogenesis can be important for the development of antiviral strategies.
|Feldman, Emily R; Kara, Mehmet; Oko, Lauren M et al. (2016) A Gammaherpesvirus Noncoding RNA Is Essential for Hematogenous Dissemination and Establishment of Peripheral Latency. mSphere 1:|
|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|
|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|
|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|
|Jain, Vaibhav; Plaisance-Bonstaff, Karlie; Sangani, Rajnikumar et al. (2016) A Toolbox for Herpesvirus miRNA Research: Construction of a Complete Set of KSHV miRNA Deletion Mutants. Viruses 8:|
|Hu, Minmin; Wang, Cong; Li, Wan et al. (2015) A KSHV microRNA Directly Targets G Protein-Coupled Receptor Kinase 2 to Promote the Migration and Invasion of Endothelial Cells by Inducing CXCR2 and Activating AKT Signaling. PLoS Pathog 11:e1005171|
|Verma, Dinesh; Li, Da-Jiang; Krueger, Brian et al. (2015) Identification of the physiological gene targets of the essential lytic replicative Kaposi's sarcoma-associated herpesvirus ORF57 protein. J Virol 89:1688-702|
|Choi, Hong Seok; Jain, Vaibhav; Krueger, Brian et al. (2015) Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Induces the Oncogenic miR-17-92 Cluster and Down-Regulates TGF-? Signaling. PLoS Pathog 11:e1005255|
|George, Jeffy; Lewis, Mark G; Renne, Rolf et al. (2015) Suppression of transforming growth factor ? receptor 2 and Smad5 is associated with high levels of microRNA miR-155 in the oral mucosa during chronic simian immunodeficiency virus infection. J Virol 89:2972-8|
|Cao, Subing; Strong, Michael J; Wang, Xia et al. (2015) High-throughput RNA sequencing-based virome analysis of 50 lymphoma cell lines from the Cancer Cell Line Encyclopedia project. J Virol 89:713-29|
Showing the most recent 10 out of 25 publications