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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Microbiol. | doi: 10.3389/fmicb.2019.02692

Epstein-Barr Virus (EBV) Latent Membrane Protein 1 (LMP1) Regulates Host B Cell miR-155 and its Target FOXO3a via PI3K p110a Activation

 Olivia Hatton1*,  Madison Alexander1, Melanie Mandell1,  Carissa Sherman1, Madeline M. Smith1,  Madeline W. Stesney1, Sin T. Hui2, Gillian Dohrn1, Joselinne Medrano1,  Kurt Ringwalt1, Aleishia Harris-Arnold2, 3, Eden M. Maloney2, 3,  Sheri M. Krams2, 3 and  Olivia M. Martinez2, 3*
  • 1Department of Molecular Biology, Colorado College, United States
  • 2Department of Surgery, Division of Abdominal Transplantation, School of Medicine, Stanford University, United States
  • 3Stanford Immunology, Stanford University, United States

Epstein-Barr Virus (EBV) is associated with potentially fatal lymphoproliferations such as post-transplant lymphoproliferative disorder (PTLD), a serious complication of transplantation. The viral mechanisms underlying the development and maintenance of EBV+ B cell lymphomas remain elusive, but represent attractive therapeutic targets. EBV modulates the expression of host microRNAs (miRs), non-coding RNAs that regulate gene expression, to promote survival of EBV+ B cell lymphomas. Here, we examined how the primary oncogene of EBV, latent membrane protein 1 (LMP1), regulates host miRs using an established model of inducible LMP1 signaling. LMP1 derived from the B95.8 lab strain or PTLD induced expression of the oncogene miR-155. However, PTLD variant LMP1 lost the ability to upregulate the tumor suppressor miR-193. Small molecule inhibitors (SMI) of p38 MAPK, NF-B, and PI3K p110 inhibited upregulation of miR-155 by B95.8 LMP1; no individual SMI significantly reduced upregulation of miR-155 by PTLD variant LMP1. miR-155 was significantly elevated in EBV+ B cell lymphoma cell lines and associated exosomes and inversely correlated with expression of the miR-155 target FOXO3a in cell lines. Finally, LMP1 reduced expression of FOXO3a, which was rescued by a PI3K p110 SMI. Our data indicate that tumor variant LMP1 differentially regulate host B cell miR expression, suggesting viral genotype as an important consideration for the treatment of EBV+ B cell lymphomas. Notably, we demonstrate a novel mechanism in which LMP1 supports the regulation of miR-155 and its target FOXO3a in B cells through activation of PI3K p110. This mechanism expands on the previously established mechanisms by which LMP1 regulates miR-155 and FOXO3a, and may represent both rational therapeutic targets and biomarkers for EBV+ B cell lymphomas.

Keywords: Epstein-Barr virus, ebv, Latent membrane protein 1, LMP1, microRNA, miR- 155, FoxO3a, PI3K

Received: 01 Sep 2019; Accepted: 06 Nov 2019.

Copyright: © 2019 Hatton, Alexander, Mandell, Sherman, Smith, Stesney, Hui, Dohrn, Medrano, Ringwalt, Harris-Arnold, Maloney, Krams and Martinez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Olivia Hatton, Colorado College, Department of Molecular Biology, Colorado Springs, 80903, Colorado, United States, olivia.hatton@coloradocollege.edu
Prof. Olivia M. Martinez, School of Medicine, Stanford University, Department of Surgery, Division of Abdominal Transplantation, Stanford, California, United States, omm@stanford.edu