دورية أكاديمية
High-throughput sequencing analysis of a 'hit and run' cell and animal model of KSHV tumorigenesis.
العنوان: | High-throughput sequencing analysis of a 'hit and run' cell and animal model of KSHV tumorigenesis. |
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المؤلفون: | Julian Naipauer, Daria Salyakina, Guy Journo, Santas Rosario, Sion Williams, Martin Abba, Meir Shamay, Enrique A Mesri |
المصدر: | PLoS Pathogens, Vol 16, Iss 6, p e1008589 (2020) |
بيانات النشر: | Public Library of Science (PLoS), 2020. |
سنة النشر: | 2020 |
المجموعة: | LCC:Immunologic diseases. Allergy LCC:Biology (General) |
مصطلحات موضوعية: | Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5 |
الوصف: | Kaposi's sarcoma (KS), is an AIDS-associated neoplasm caused by the KS herpesvirus (KSHV/ HHV-8). KSHV-induced sarcomagenesis is the consequence of oncogenic viral gene expression as well as host genetic and epigenetic alterations. Although KSHV is found in all KS-lesions, the percentage of KSHV-infected (LANA+) spindle-cells of the lesion is variable, suggesting the existence of KS-spindle cells that have lost KSHV and proliferate autonomously or via paracrine mechanisms. A mouse model of KSHVBac36-driven tumorigenesis allowed us to induce KSHV-episome loss before and after tumor development. Although infected cells that lose the KSHV-episome prior to tumor formation lose their tumorigenicity, explanted tumor cells that lost the KSHV-episome remained tumorigenic. This pointed to the existence of virally-induced irreversible oncogenic alterations occurring during KSHV tumorigenesis supporting the possibility of hit and run viral-sarcomagenesis. RNA-sequencing and CpG-methylation analysis were performed on KSHV-positive and KSHV-negative tumors that developed following KSHV-episome loss from explanted tumor cells. When KSHV-positive cells form KSHV-driven tumors, along with viral-gene upregulation there is a tendency for hypo-methylation in genes from oncogenic and differentiation pathways. In contrast, KSHV-negative tumors formed after KSHV-episome loss, show a tendency towards gene hyper-methylation when compared to KSHV-positive tumors. Regarding occurrence of host-mutations, we found the same set of innate-immunity related mutations undetected in KSHV-infected cells but present in all KSHV-positive tumors occurring en exactly the same position, indicating that pre-existing host mutations that provide an in vivo growth advantage are clonally-selected and contribute to KSHV-tumorigenesis. In addition, KSHV-negative tumors display de novo mutations related to cell proliferation that, together with the PDGFRAD842V and other proposed mechanism, could be responsible for driving tumorigenesis in the absence of KSHV-episomes. KSHV-induced irreversible genetic and epigenetic oncogenic alterations support the possibility of "hit and run" KSHV-sarcomagenesis and point to the existence of selectable KSHV-induced host mutations that may impact AIDS-KS treatment. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 1553-7366 1553-7374 |
Relation: | https://doaj.org/toc/1553-7366; https://doaj.org/toc/1553-7374 |
DOI: | 10.1371/journal.ppat.1008589 |
URL الوصول: | https://doaj.org/article/a351f3e40e5d4b26b562a56634b6d215 |
رقم الأكسشن: | edsdoj.351f3e40e5d4b26b562a56634b6d215 |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 15537366 15537374 |
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DOI: | 10.1371/journal.ppat.1008589 |