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dc.date.accessioned | 2020-10-29T13:51:24Z | |
dc.date.available | 2020-10-29T13:51:24Z | |
dc.date.issued | 2020 | |
dc.identifier.uri | http://sedici.unlp.edu.ar/handle/10915/107926 | |
dc.description.abstract | 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” KSHVsarcomagenesis and point to the existence of selectable KSHV-induced host mutations that may impact AIDS-KS treatment. | en |
dc.language | en | es |
dc.subject | cancers and neoplasms | es |
dc.subject | DNA methylation | es |
dc.subject | carcinogenesis | es |
dc.subject | malignant tumors | es |
dc.subject | epigenetics | es |
dc.subject | viral gene expression | es |
dc.subject | virus effects on host gene expression | es |
dc.subject | mammalian genomics | es |
dc.title | High-throughput sequencing analysis of a "hit and run" cell and animal model of KSHV tumorigenesis | en |
dc.type | Articulo | es |
sedici.identifier.uri | http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7357787&blobtype=pdf | es |
sedici.identifier.uri | https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008589 | es |
sedici.identifier.other | pmid:32603362 | es |
sedici.identifier.other | pmcid:PMC7357787 | es |
sedici.identifier.other | http://dx.doi.org/10.1371/journal.ppat.1008589 | es |
sedici.identifier.issn | 1553-7374 | es |
sedici.creator.person | Naipauer, Julian | es |
sedici.creator.person | Salyakina, Daria | es |
sedici.creator.person | Journo, Guy | es |
sedici.creator.person | Rosario, Santas | es |
sedici.creator.person | Williams, Sion | es |
sedici.creator.person | Abba, Martín Carlos | es |
sedici.creator.person | Shamay, Meir | es |
sedici.creator.person | Mesri, Enrique A. | es |
sedici.subject.materias | Medicina | es |
sedici.description.fulltext | true | es |
mods.originInfo.place | Facultad de Ciencias Médicas | es |
mods.originInfo.place | Centro de Investigaciones Inmunológicas Básicas y Aplicadas | es |
sedici.subtype | Articulo | es |
sedici.rights.license | Creative Commons Attribution 4.0 International (CC BY 4.0) | |
sedici.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
sedici.description.peerReview | peer-review | es |
sedici.relation.journalTitle | PLoS Pathogens | es |
sedici.relation.journalVolumeAndIssue | vol. 16, no. 6 | es |