At least one in six human cancers is linked to viral infection. A portion of these can be attributed to Epstein-Barr virus (EBV), a ubiquitous DNA tumor virus associated with cancers such as Burkitt's, Hodgkin's, and diffuse large B cell lymphomas. During infection, EBV expresses viral microRNAs (miRNAs), and recent studies have demonstrated an important role for the EBV miRNAs as well as the cellular oncogenic miRNAs upregulated by EBV infection in the B cell transformation process. Furthermore, several EBV miRNAs share sequence homology with cellular miRNAs that are dysregulated in cancers and potentially, these viral miRNAs can tie into and alter existing miRNA-regulated networks. The miRNA targets involved in transformation are not yet defined, and thus, systemically identifying the genes regulated by miRNAs in EBV-infected cells is essential to understanding their contributions to viral oncogenesis and their roles during the EBV life cycle. Experiments outlined here combine state-of-the-art techniques from the multidisciplinary fields of miRNA biology, virology, and bioinformatics to comprehensively interrogate the miRNA targetome and examine the transcriptional landscape of EBV-infected B cells in order to extract critical genes and pathways influenced by viral and cellular miRNAs. These studies will be carried out using an EBV-driven in vitro B cell transformation model in addition to patient-derived EBV+ B cell tumors. To successfully carry out my studies, I require new training in both EBV biology and bioinformatics, and have accordingly assembled a scientific advisory committee to guide me in establishing and/or further developing several of the essential methodologies. The K99/R00 award will provide me both resources and time for new training during the mentored phase in order to learn fundamental de novo infection techniques and generate additional data and computational tools to be used in my own laboratory during the independent phase. By integrating the miRNA targetome data, transcriptome data, and phenotypic data generated through these experiments, I hope to elucidate the mechanisms by which miRNAs, particularly EBV miRNAs, contribute to persistent viral infection and the development of lymphoma. Finally, since EBV expresses not only viral miRNAs but further alters expression of oncogenic cellular miRNAs that have been linked to many cancers not associated with viral infection, these studies will potentially provide important information that can be extended to other cancer models and provide insight into the overall mechanisms governing miRNA-mediated gene regulation in cancers.

Public Health Relevance

One in six cancers can be linked to viral infection, and a portion of these can be attributed to infection with Epstein-Barr virus (EBV). EBV is a ubiquitous virus, infecting >90% of adults worldwide. Primary infection is commonly asymptomatic or presents as mononucleosis which resolves within a few weeks;however, in certain circumstances, life-long, latent infection can lead to epithelial and lymphoid malignancies, including lymphoma. Recent studies demonstrate roles for both EBV-encoded microRNAs and EBV-induced cellular miRNAs in B cell transformation and survival in vitro. The goal of this proposal is to comprehensively identify and characterize critical miRNA-regulated genes during EBV infection of B cells in order to understand their contributions to viral oncogenesis. Furthermore, in vitro EBV infection of B cells provides us a valuable model system to investigate the molecular mechanisms driving the development and progression of uncontrolled B cell proliferation. These studies thus have the potential to uncover novel therapeutic targets for not only EBV- associated cancers but also lymphoproliferative diseases in general. The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K99)
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Study Section
Subcommittee B - Comprehensiveness (NCI)
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Schmidt, Michael K
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Oregon Health and Science University
Schools of Medicine
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Hancock, Meaghan H; Skalsky, Rebecca L (2018) Roles of Non-coding RNAs During Herpesvirus Infection. Curr Top Microbiol Immunol 419:243-280
Skalsky, Rebecca L (2017) Analysis of Viral and Cellular MicroRNAs in EBV-Infected Cells. Methods Mol Biol 1532:133-146
Skinner, Camille M; Ivanov, Nikita S; Barr, Sarah A et al. (2017) An Epstein-Barr Virus MicroRNA Blocks Interleukin-1 (IL-1) Signaling by Targeting IL-1 Receptor 1. J Virol 91:
Skalsky, Rebecca L; Cullen, Bryan R (2015) EBV Noncoding RNAs. Curr Top Microbiol Immunol 391:181-217