title: Viral oncomiR spreading between B and T cells is employed by Kaposi's sarcoma herpesvirus to induce non-cell-autonomous target gene regulation.
abstract: The two human lymphotrophic γ-herpesviruses, Kaposi's sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV), are a recognized cause of human cancer, encoding multiple miRs that are major players in carcinogenesis. Previously, we discovered that EBV-encoded miRs transfer between infected B and T lymphocytes. To further explore the biological significance of the spreading of γ-herpesvirus-encoded miRs on carcinogenesis, we focused on KSHV-miR-K12-11 (miR-K12-11) that is unique in having an identical seed sequence with the oncomiR hsa-miR-155, implicated in B cell lymphomas development. Here, we show for the first time that miR-K12-11 transfers in vitro from KSHV-infected BCBL-1 and BC-1 lymphoma lines to T cells. The transferred miR-K12-11 is active in the adopting T cells and binds its canonical target, the 3'-UTR of BACH1. Importantly, we show that the transfer of miR-K12-11 from BCBL-1 to Jurkat cells correlates with inhibition of the innate type-I interferons response to viral dsRNAs downstream of IKKε, a validated miR-K12-11 target. Finally, we show that miR-K12-11 spreading is not reduced by blocking the classical ceramide-dependent exosome secretion pathway. In summary, we report for the first time that intercellular viral oncomiR spreading is an additional mechanism employed by KSHV to inhibit host anti-viral immunity and consequently promote oncogenesis.
authors.affiliation: Sheba Cancer Research Center, Chaim Sheba Academic Medical Center, Tel Hashomer, Ramat Gan 5262100, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel.|Department of Neurobiology, The George S. Wise Faculty of Life Sciences & Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 6997801, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Rainy
authors.affiliation: Sheba Cancer Research Center, Chaim Sheba Academic Medical Center, Tel Hashomer, Ramat Gan 5262100, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel.
authors.forename: Morad
authors.initials: M
authors.lastname: Zayoud
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences & Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 6997801, Israel.
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences & Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 6997801, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Rechavi
authors.affiliation: Sheba Cancer Research Center, Chaim Sheba Academic Medical Center, Tel Hashomer, Ramat Gan 5262100, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel.
authors.forename: Itamar
authors.initials: I
authors.lastname: Goldstein
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism* / Q000821:virology; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D019169:Jurkat Cells; D008223:Lymphoma / Q000235:genetics / Q000473:pathology / Q000821:virology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D014162:Transfection / Q000379:methods
chemical_list: D020413:3' Untranslated Regions; C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012367:RNA, Viral
keywords: herpesviruses; lymphoma; microRNAs; oncomiRs; viral carcinogenesis