High-throughput sequencing analysis of a "hit and run" cell and animal model of KSHV tumorigenesis
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-inf...
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| Autores principales: | , , , , , , , |
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| Formato: | Articulo |
| Lenguaje: | Inglés |
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2020
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| Acceso en línea: | http://sedici.unlp.edu.ar/handle/10915/107926 http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7357787&blobtype=pdf https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008589 |
| Aporte de: |
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I19-R120-10915-107926 |
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dspace |
| institution |
Universidad Nacional de La Plata |
| institution_str |
I-19 |
| repository_str |
R-120 |
| collection |
SEDICI (UNLP) |
| language |
Inglés |
| topic |
Medicina cancers and neoplasms DNA methylation carcinogenesis malignant tumors epigenetics viral gene expression virus effects on host gene expression mammalian genomics |
| spellingShingle |
Medicina cancers and neoplasms DNA methylation carcinogenesis malignant tumors epigenetics viral gene expression virus effects on host gene expression mammalian genomics Naipauer, Julian Salyakina, Daria Journo, Guy Rosario, Santas Williams, Sion Abba, Martín Carlos Shamay, Meir Mesri, Enrique A. High-throughput sequencing analysis of a "hit and run" cell and animal model of KSHV tumorigenesis |
| topic_facet |
Medicina cancers and neoplasms DNA methylation carcinogenesis malignant tumors epigenetics viral gene expression virus effects on host gene expression mammalian genomics |
| description |
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 <i>in vivo</i> growth advantage are clonally-selected and contribute to KSHV-tumorigenesis. In addition, KSHV-negative tumors display <i>de novo</i> 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. |
| format |
Articulo Articulo |
| author |
Naipauer, Julian Salyakina, Daria Journo, Guy Rosario, Santas Williams, Sion Abba, Martín Carlos Shamay, Meir Mesri, Enrique A. |
| author_facet |
Naipauer, Julian Salyakina, Daria Journo, Guy Rosario, Santas Williams, Sion Abba, Martín Carlos Shamay, Meir Mesri, Enrique A. |
| author_sort |
Naipauer, Julian |
| title |
High-throughput sequencing analysis of a "hit and run" cell and animal model of KSHV tumorigenesis |
| title_short |
High-throughput sequencing analysis of a "hit and run" cell and animal model of KSHV tumorigenesis |
| title_full |
High-throughput sequencing analysis of a "hit and run" cell and animal model of KSHV tumorigenesis |
| title_fullStr |
High-throughput sequencing analysis of a "hit and run" cell and animal model of KSHV tumorigenesis |
| title_full_unstemmed |
High-throughput sequencing analysis of a "hit and run" cell and animal model of KSHV tumorigenesis |
| title_sort |
high-throughput sequencing analysis of a "hit and run" cell and animal model of kshv tumorigenesis |
| publishDate |
2020 |
| url |
http://sedici.unlp.edu.ar/handle/10915/107926 http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7357787&blobtype=pdf https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008589 |
| work_keys_str_mv |
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Repositorios |
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