Bcl-2 and p53 immunoprofile in kaposi’s sarcoma

Pillay, Pavitra; Chetty, Runjan; Reddy, Roshilla

doi:10.1053/paor.1999.0017

Cited by 15 publications

(10 citation statements)

References 11 publications

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“…In hit-and-run scenario, cells are irreversibly transformed by KSHV and are able to sustain tumors in the absence of virus. This is consistent with some reports that have identified the presence of host oncogenic mutations in KS lesions (Nicolaides et al, 1994; Pillay et al, 1999). Yet the possibility of KSHV induced hit-and-run tumorigenesis and its mechanistic underpinnings have not been yet firmly established.…”

Section: Introductionsupporting

confidence: 93%

RNA-sequencing analysis of a multistep and hit-and-run cell and animal model of KSHV tumorigenesis reveal the roles of mutations, CpG methylation, and viral-infection footprints in oncogenesis

Naipauer¹,

Salyakina

Journo

et al. 2019

Preprint

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Human viral oncogenesis is the consequence of cell transformation mediated by virally encoded oncogenes in combination with host oncogenic alterations. Kaposi’s sarcoma (KS), caused by the Kaposi’s sarcoma-associated herpes virus (KSHV), is an AIDS-associated cancer characterized by angiogenesis and spindle-cells proliferation. KSHV-infected KS lesions are composed of latently-infected cells, as well as cells expressing lytic genes that have been implicated in the development of the KS angioproliferative phenotype. The existence of KS lesions with varying levels of KSHV-infected cells suggests also the existence of virus-independent “hit-and-run” mechanisms of sarcomagenesis, whereby viral infection irreversibly induce genetic or epigenetic oncogenic alterations in host cells. We have integrated genetic mutations, changes in expression signatures and methylation analysis to dissect genetic and epigenetic signaling pathways in an unbiased manner in the mECK36 mouse model of KSHV tumorigenesis. Pathway analysis of differential expressed genes (DEGs) showed KSHV lytic switch, DNA methylation and Epigenetic as the most regulated pathways during KSHV-dependent in vivo tumorigenesis. Methylation analysis data indicates that during the development of KSHV-infected tumors the most changes were towards hypo-methylation of tissues specific genes and oncogenic signature pathways, on the other hand during viral loss and development of KSHV-negative tumors changes are towards hyper-methylation. Mutational analysis of KSHV-infected cells and tumors revealed a set of mutations, including mutations in three inflammasome-related IFN response genes, that were absent in KSHV-infected cells but present in all KSHV-infected tumors in the same loci pointing to clonal selection “in vivo”. This result suggests that in the context of in vivo tumorigenesis both these mutations and the virus may determine tumor growth. On the other hand, clustering analysis of mutations driving KSHV-negative tumors reveal a network comprising PDGFRA D842V, Pak1 and Nucleolin mutations implicated in cell proliferation. Our results have uncovered novel specific aspects of the interplay between host oncogenic alterations and virus-induced transcriptional effects as well as the epigenetic changes induced by KSHV infection and tumorigenesis. The existence virally-induced irreversible genetic and epigenetic oncogenic alterations support the possibility for hit-and-run KSHV sarcomagenesis which is consistent with pathological and clinical findings.AUTHOR SUMMARYWe performed whole genome RNA sequencing and CpG DNA methylation analysis in a mouse bone-marrow endothelial-lineage cells (mEC) transfected with the KSHVBac36 (mECK36 cells), that are able to form KSHV-infected tumors in nude mice, which were thoroughly characterized as KS-like tumors. This unique model allowed us to dissect genetic and epigenetic mechanisms of KSHV dependent and hit-and-run sarcomagenesis. We found that during KSHV in vivo lytic switch and KSHV-dependent tumorigenesis DNA methylation and Epigenetic regulation are among the most host-regulated pathways. CpG DNA methylation analysis during transformation supports the notion that loss of methylation (hypo-methylation) is the major epigenetic change during this process. Sequence analysis of KSHV-positive tumors revealed that KSHV tumorigenesis not only selects for the presence of the virus but also pre-existing host mutations that allow the KSHV oncovirus to express the oncogenic lytic program and creates a permissive environment of inflammation and viral tumorigenesis providing a selective advantage in vivo.

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Section: Introductionsupporting

confidence: 93%

RNA-sequencing analysis of a multistep and hit-and-run cell and animal model of KSHV tumorigenesis reveal the roles of mutations, CpG methylation, and viral-infection footprints in oncogenesis

Naipauer¹,

Salyakina

Journo

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…The currently accepted interpretation of these data is that KS starts as a hyperplastic polyclonal lesion that is associated with inflammation and KSHV infection that could give rise, under specific circumstances like immunosuppression or other selective pressures, to clonal metastatic lesions. Supporting the idea that KS is only truly neoplastic in advanced stages is the observation that cellular oncogenic alterations, such as p53 and KRAS mutations or BCL-2 overexpression, as well as gene copy number changes, occur only in late-stage advanced disease 58, 59, 60 . Therefore, KS has features reminiscent of post-transplant lymphoproliferative disorders, which are EBV-driven B cell proliferations progressing from polyclonal hyperplasia to monoclonal tumours, and eventually to malignant lymphoma with oncogene and tumour suppressor alterations 61 .…”

Section: Reactive Inflammation or True Neoplasm?mentioning

confidence: 99%

Kaposi's sarcoma and its associated herpesvirus

2010

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Kaposi’s sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi’s sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV8)) is the infectious cause of this neoplasm. In this Review we describe the epidemiology of KS and KSHV, and the insights into the remarkable mechanisms through which KSHV can induce KS that have been gained in the past 16 years. KSHV latent transcripts, such as latency-associated nuclear antigen (LANA), viral cyclin, viral FLIP and viral-encoded microRNAs, drive cell proliferation and prevent apoptosis, whereas KSHV lytic proteins, such as viral G protein-coupled receptor, K1 and virally encoded cytokines (viral interleukin-6 and viral chemokines) further contribute to the unique angioproliferative and inflammatory KS lesions through a mechanism called paracrine neoplasia.

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“…However, the expression of p53 varies in different stages of KS progression. The expression of p53 was hardly detectable in the early stage of KS, but the percentage of p53-positive cells increased in the more advanced stage (2,18,34,45,55,62,71). Apparently, the absence of p53 results in a disadvantage for cells in controlling the aberrant proliferation that is induced by KSHV viral proteins, such as K-cyclin.…”

Section: Discussionmentioning

confidence: 98%

Kaposi's Sarcoma-Associated Herpesvirus K-Cyclin Interacts with Cdk9 and Stimulates Cdk9-Mediated Phosphorylation of p53 Tumor Suppressor

Chang

2008

J Virol

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K-cyclin, encoded by Kaposi's sarcoma-associated herpesvirus, has previously been demonstrated to activate cyclin-dependent kinase 6 (Cdk6) to induce the phosphorylation of various cell cycle regulators. In this study, we identified Cdk9 as a new K-cyclin-associated Cdk and showed that K-cyclin interacted with Cdk9 through its basic domain. We hypothesized that K-cyclin served as a regulatory subunit for the activity of Cdk9. Recent reports show that Cdk9 phosphorylates tumor suppressor p53, and we found that the K-cyclin/Cdk9 interaction greatly enhanced the kinase activity of Cdk9 toward p53. The phosphorylation site(s) of K-cyclin/Cdk9 kinase complexes was mapped in the transactivation domain of p53. We showed that the ectopic expression of K-cyclin led to a sustained increase of p53 phosphorylation on Ser 33 in vivo, and the phosphorylation could be inhibited by a dominant negative Cdk9 mutant, dn-Cdk9. Using p53-positive U2OS and p53-null SaOS2 cells, we demonstrated that K-cyclin-induced growth arrest was associated with the presence of p53. In addition, K-cyclin-induced p53-dependent growth arrest was rescued by the dn-Cdk9-or Cdk9-specific short hairpin RNA in SaOS2 cells. Together, our findings for the first time demonstrated the interaction of K-cyclin and Cdk9 and revealed a new molecular link between K-cyclin and p53.

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Bcl-2 and p53 immunoprofile in kaposi’s sarcoma

Cited by 15 publications

References 11 publications

RNA-sequencing analysis of a multistep and hit-and-run cell and animal model of KSHV tumorigenesis reveal the roles of mutations, CpG methylation, and viral-infection footprints in oncogenesis

RNA-sequencing analysis of a multistep and hit-and-run cell and animal model of KSHV tumorigenesis reveal the roles of mutations, CpG methylation, and viral-infection footprints in oncogenesis

Kaposi's sarcoma and its associated herpesvirus

Kaposi's Sarcoma-Associated Herpesvirus K-Cyclin Interacts with Cdk9 and Stimulates Cdk9-Mediated Phosphorylation of p53 Tumor Suppressor

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