Ontology highlight
ABSTRACT:
PROVIDER: PRJEB15877 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Idiomarina zobellii KMM 231 genome sequencing
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Project description:Idiomarina zobellii strain:KMM 231 Genome sequencing and assembly
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Project description:Idiomarina abyssalis KMM 227 genome sequencing
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Project description:The hallmark of Kaposi’s sarcoma (KS), the most common cancer in HIV-infected patients caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, is hyperinflammation. However, the role of inflammation and the mechanism of induction of inflammation in KSHV-induced cancer remain unclear. In a previous high-throughput screening against KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents. Among them, dexamethasone, a common anti-inflammatory corticosteroid, functions through binding to and activating glucocorticoid receptor (GR). In this study, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, the interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family, implicated in a wide variety of inflammatory diseases, were the most induced and suppressed cytokines in KSHV-transformed KMM cells compared to the matched primary MM cells, respectively. By using reverse genetics, we showed that KSHV-encoded miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, the GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Importantly, dexamethasone treatment inhibited cell proliferation, and colony formation in softagar of KMM cells but had a minimal effect on MM cells. Consequently, dexamethasone suppressed the initiation and growth of KS-like KMM tumors in mice. Mechanistically, dexamethasone suppressed IL-1α expression but induced IL-1Ra expression. Treatment with recombinant IL-1α protein was sufficient to rescue the inhibitory effect of dexamethasone while overexpression of IL-1Ra alone caused a weak growth inhibition of KMM cells. Furthermore, dexamethasone induced IκBα expression resulting in the inhibition of the classical and alternative NF-kB pathways and IL-1α expression. Taken together, these results revealed the important role of IL-1 signaling pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling. This study determined the mechanism of inflammation in KSHV-induced oncogenesis and identified IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies.
2023-12-31 | GSE242172 | GEO
Project description:RNA alternative splicing is a fundamental cellular process implicated in cancer development. Kaposi’s sarcoma-associated herpesvirus (KSHV), the etiological agent of multiple human malignancies, including Kaposi’s sarcoma (KS), remains a significant concern, particularly in AIDS patients. A CRISPR-Cas9 screening of matched primary rat mesenchymal stem cells (MM) and KSHV-transformed MM cells (KMM) identified key splicing factors involved in KSHV-induced cellular transformation. To elucidate the mechanisms by which KSHV-driven splicing reprogramming mediates cellular transformation, we performed transcriptomic sequencing, identifying 131 differential alternative splicing transcripts, with exon skipping as the predominant event. Notably, these transcripts were enriched in vascular permeability, multiple metabolic pathways and ERK1/2 signaling cascades, which play key roles in KSHV-induced oncogenesis. Further analyses of cells infected with KSHV mutants lacking latent genes including vFLIP, vCyclin and viral miRNAs, as well as cells overexpressing LANA, revealed their involvement in alternative splicing regulation. Among the identified splicing factors, FAM50A, a component of the spliceosome complex C, was found to be crucial for KSHV-mediated transformation. FAM50A knockout resulted in distinct splicing profiles in both MM and KMM cells, and significantly inhibited KSHV-driven proliferation, cellular transformation and tumorigenesis. Mechanistically, FAM50A knockout altered SHP2 splicing, promoting an isoform with enhanced enzymatic activity that led to reduced STAT3 Y705 phosphorylation in KMM cells. These findings reveal a novel paradigm in which KSHV hijacks host splicing machinery, specifically FAM50A-mediated SHP2 splicing, to sustain STAT3 activation and drive oncogenic transformation.
2025-04-26 | GSE295315 | GEO