KSHV-induced iNOS in Kaposi’s Sarcoma tumors and mouse model
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE222527 | GEO | 2023/07/14
REPOSITORIES: GEO
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Project description:The Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s Sarcoma (KS), which preferentially arise in immunocompromised patients but lack of effective therapeutic options. We have previously shown that KSHV or viral protein LANA can upregulate the glycoprotein CD147 (Emmprin) to induce primary endothelial cell invasiveness, which also requires PI3K/Akt and MAPK activation of VEGF production. In the current study, we first time identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among these downstream genes, ADAMTS1 and 9, two specific metalloproteases are strongly expressed in AIDS-KS tissues and contributed to KSHV-infected cell invasiveness through regulation of related cytokines production and respective receptors expression. By using a nude mice KS-like model, we found that targeting CD147 and downstream ADAMTSs proteins significantly suppressed KSHV-related tumorigenesis in vivo, which is potentially through impairing extracellular matrix (ECM) formation in tumor microenvironment. Taken together, we think that targeting CD147 and related proteins may represent a promising therapeutic strategy against KSHV-related malignancies.
2016-05-31 | GSE69067 | GEO
Project description:Transfection of a Kaposi's sarcoma (KS) herpesvirus (KSHV) Bacterial Artificial Chromosome (KSHVBac36) into mouse bone marrow endothelial lineage cells generated a cell (mECK36) that induced KS-like tumors in mice. mECK36 formed KSHV-harboring vascularized spindle-cell sarcomas that were LANA+ and displayed a KSHV and host transcriptomes reminiscent of KS tumors. Keywords: Cell type comparison
2007-01-01 | GSE6482 | GEO
Project description:Transfection of a Kaposi's sarcoma (KS) herpesvirus (KSHV) Bacterial Artificial Chromosome (KSHVBac36) into mouse bone marrow endothelial lineage cells generated a cell (mECK36) that induced KS-like tumors in mice. mECK36 formed KSHV-harboring vascularized spindle-cell sarcomas that were LANA+ and displayed a KSHV and host transcriptomes reminiscent of KS tumors. Experiment Overall Design: There are three biological replicates per sample. Tumors (mKS) were compared the the human KS signature. mECK36 and mEC-V were compared to putative BM lineage cells.
2008-06-14 | E-GEOD-6482 | biostudies-arrayexpress
Project description:The Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), the most common HIV/AIDS-associated tumor worldwide. Involvement of the oral cavity portends a poor prognosis for patients with KS, but mechanisms for KSHV regulation of the oral tumor microenvironment are largely unknown. Infiltrating fibroblasts are found with KS lesions, and KSHV establishes latent infection within human primary fibroblasts in vitro, but contributions for KSHV-infected fibroblasts to the KS microenvironment have not been previously characterized. In the present study, we used Illumina microarray to detect the global gene profile altered in KSHV-infected primary human fibroblasts (PDLF and HGF) isolated from the oral cavity.
2017-01-01 | GSE79548 | GEO
Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS). In sub-Saharan Africa, the high prevalence of both HIV-1 and KSHV has made KS a leading cancer in the region, associated with poor prognosis and high mortality due to late medical presentation and advanced disease stages. A better understanding of the cellular and viral transcriptome profiles during neoplastic growth will aid in the definition of biomarkers and cellular functions associated with KS tumorigenesis and progression. Our approach is to examine the transcriptome profile in actual KS lesions versus non-cancer tissues from the same individual for a total of four male African epidemic KS patients. These patients have undetectable HIV-1 plasma viral load after successful anti-retroviral therapy. Our results capture the cellular complexity of in vivo lesion environment and provide a marked contrast to those derived from in vitro monoculture models. The findings demonstrate that latency and immune modulation related functions dominate the viral gene expression pattern. Moreover, KSHV significantly affected the cellular transcriptome profile with genes involved in lipid and glucose metabolism disorder pathways being the most substantially dysregulated. Despite the implied infiltration of immune cells into the lesions as predicted by CIBERSORT, KS tumor continued to progress, suggesting immunological dysfunction in these KS patients despite control of HIV-1 viremia. Lastly, there is limited overlap of our in vivo dataset with in vitro studies, suggesting a limitation of in vitro KS models.
2018-01-17 | GSE100684 | GEO
Project description:Kaposi's sarcoma (KS), is an AIDS-associated neoplasm caused by the KS herpesvirus (KSHV/ HHV-8). KSHV-sarcomagenesis is the consequence of oncogenic viral gene expression as well as host genetic and epigenetic alterations. Although KSHV is invariably found in all KS lesions, the percentage of KSHV-infected (LANA+) spindle-cells of the lesion is variable, suggesting the existence of paracrine oncogenic mechanisms and/or spindle cells that have lost KSHV. A mouse model of KSHVBac36-driven tumorigenesis allowed us to induce KSHV-episome loss before and after tumor development. Although cells that lose the KSHV episome prior to tumor formation lose their tumorigenicity, explanted KSHV positive tumor cells that lost the KSHV episome remained tumorigenic. This pointed to the existence of virally-induced irreversible oncogenic alterations occurring during KSHV-tumor formation that support the possibility of hit and run viral sarcomagenesis. RNA sequencing and CpG-methylation analysis were performed on KSHV positive and negative cells, 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, 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, were responsible for driving tumorigenesis in absence of the KSHV-episomes. KSHV-induced irreversible genetic and epigenetic oncogenic alterations support the possibility of “hit and run” KSHV-sarcomagenesis consistent with the presence of LANA-negative spindle-cells in KS lesions.
2020-04-16 | GSE148741 | GEO
Project description:Kaposi's sarcoma (KS), is an AIDS-associated neoplasm caused by the KS herpesvirus (KSHV). A mouse model of KSHV-dependent tumorigenicity, allowed us to induce KSHV viral-episome loss following tumor development to test the plausibility of “hit and run” mechanism by KSHV. RNA-seq-transcriptome analysis and CpG-methylation were performed on KSHV positive cells, KSHV positive tumors and tumors that developed following viral-episome loss. During KSHV tumorigenesis, hypo-methylation was detected of oncogenic and differentiation pathways. In contrast, during tumorigenesis following KSHV-episome loss, a tendency towards hyper-methylation was detected. We found the same set of innate-immunity related mutations undetected in KSHV-infected cells but present in all KSHV-positive tumors, indicating that pre-existing host mutations that provide an in vivo growth advantage are clonally-selected and contribute to KSHV-tumorigenesis. We found de novo mutations related to cell proliferation that, together with the PDGFRAD842V, were responsible for driving tumorigenesis in absence of the KSHV-episomes. Virally-induced irreversible genetic and epigenetic oncogenic alteration supports the possibility of “hit and run” KSHV-sarcomagenesis consistent with the existence of LANA-negative spindle-cells in KS lesions.
2020-01-23 | GSE144101 | GEO
Project description:The Kaposiâs Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposiâs Sarcoma (KS), which preferentially arise in immunocompromised patients but lack of effective therapeutic options. We have previously shown that KSHV or viral protein LANA can upregulate the glycoprotein CD147 (Emmprin) to induce primary endothelial cell invasiveness, which also requires PI3K/Akt and MAPK activation of VEGF production. In the current study, we first time identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among these downstream genes, ADAMTS1 and 9, two specific metalloproteases are strongly expressed in AIDS-KS tissues and contributed to KSHV-infected cell invasiveness through regulation of related cytokines production and respective receptors expression. By using a nude mice KS-like model, we found that targeting CD147 and downstream ADAMTSs proteins significantly suppressed KSHV-related tumorigenesis in vivo, which is potentially through impairing extracellular matrix (ECM) formation in tumor microenvironment. Taken together, we think that targeting CD147 and related proteins may represent a promising therapeutic strategy against KSHV-related malignancies. HUVEC cells were infected by KSHV or transduced by a CD147 recombinant adenoviral vector and the gene expression signature was compared to respective controls
2016-05-31 | E-GEOD-69067 | biostudies-arrayexpress
Project description:Purpose: To characterize genome-wide microRNA (miRNA) expression profiles in the context of Kaposi’s sarcoma-associated herpesvirus (KSHV)-induced oncogenesis using isogenic cell lines for a Kaposi's sarcoma (KS) xenograft model: KSHV-infected human endothelial cells (LTC) that form tumors with properties closely resembling KS lesions in nude mice and uninfected parental (TIVE) cells. Methods: miRNA expression profiles of LTC and TIVE cells were generated by deep sequencing using Illumina HiSeq 2500. The mappable reads were aligned to the human genome and miRBase using Bowtie. Results: We show, through global cellular miRNA transcriptome analysis, that KSHV infection has a profound impact on the host miRNA expression landscape, up-regulating multiple miRNAs with oncogenic roles while down-regulating many tumor suppressive miRNAs, thereby contributing to KS oncogenesis. In particular, we identify miR-127-3p as one of the most significantly down-regulated miRNAs in LTC and restoring this miRNA inhibits KSHV-induced transformation, proliferation and tumorigenesis. Conclusions: This study provides a detailed analysis of the cellular miRNA transcriptome in LTC and TIVE cells using small RNA sequencing technology. We identify significant dysregulation of cellular miRNAs with important oncogenic or tumor-suppressive functions that may be physiologically relevant to KSHV oncogenesis. Moreover, our results identify a previously unrecognized tumor suppressor function for miR-127-3p in KS, indicating that its restoration offers potential as a therapeutic intervention for KS.
2021-11-01 | GSE158936 | GEO
Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) is a g-herpesvirus which persists as circular extrachromasomal DNA in the nucleus during latent infection. During latency a limited number of viral proteins are expressed, including LANA (latency-associated nuclear antigen). LANA is a multi-functional protein known to interact with transcriptional regulators and chromatin remodelers, and to regulate the LANA and RTA promoters. We hypothesized that LANA may contribute to the establishment of latency through controlling chromatinization and histone modification of KSHV episomes. We performed ChIP-seq analysis and correlated H3K4me3, H3K27me3, polII, and LANA occupancy of the KSHV genome at nucleotide resolution. Epigenetic marks were analyzed in BCBL-1 lymphoid cells and in telomerase-immortalized vein endothelial TIVE-LTC cells. We found that the transcription active mark H3K4me3, but not silencing mark H3K27me3, was enriched at KSHV regions where LANA is bound. Co-occupancy of LANA and H3K4 was also detected on 167 host genes, of which 89 are actively transcribed. By comparing LANA occupancy with the profiling of 43 transcription factors from ENCODE, a subset of transcription factors was enriched at regions where LANA is bound, including znf143, CTCF, and Stat1. These results indicate that LANA also plays a role in modulating expression of host genes. Co-immunoprecipitation of LANA with the H3K4 methyltransferase hSET1 suggests that LANA recruits hSET1 to specific loci on the viral genome, leading to H3K4 methylation and ensuring transcription of latency-associated genes. Host gene expression may be regulated by the same mechanism. LANA binding was correlated with the distribution in the latent KSHV genome of the transcription active histone modification H3K4me3, the silencing mark H3K27me3, and RNA polymerase II, using cells of lymphoid and endothelial origin. A similar analysis was done for the human genome. Biological replicates (BR) and technical replicates (TR) were included.
2014-10-27 | E-GEOD-52421 | biostudies-arrayexpress