Project description:This SuperSeries is composed of the SubSeries listed below. Purpose: Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) causes several lymphoproliferative disorders, including KS, a common AIDS-associated malignancy. Cellular and viral microRNAs (miRNAs) have been shown to play important roles in regulating the expression of genes in oncogenesis. Herpesviruses, including KSHV, encode for miRNAs that are involved in angiogenesis, inflammation and apoptosis. A better knowledge of the miRNA-mediated pathways that regulate KSHV infection is therefore essential for an improved understanding of viral infection and pathogenesis. Methods: In this study, we used deep sequencing to analyze miRNA, both viral and human, and mRNA expression in KS tumor-derived human cells. Results: This approach revealed 153 differentially expressed human miRNAs between KSHV-positive and -negative cells. Differential expression of eight miRNAs was independently confirmed by qRT-PCR. We additionally showed that a majority (~73%) of KSHV-regulated miRNAs are down-regulated, including most members of the 14q32 miRNA cluster. Specifically, human miR-409-3p, which is known to target the pro-angiogenic growth factor angiogenin and the inflammation marker fibrinogen-beta, was significantly down-regulated in KSHV-infected cells based on deep sequencing and qRT-PCR. Despite this substantial down-regulation of cellular miRNAs, hsa-miR-708-5p was significantly up-regulated by KSHV and has been shown to directly inhibit pro-apoptotic protease Caspase-2. Finally, we evaluated to what extent there was an inverse correlation between miRNA and mRNA expression levels. Using filtered datasets, we identified relevant canonical pathways that were significantly enriched. Conclusion: Taken together, our data demonstrate that most human miRNAs affected by KSHV are repressed and our findings highlight the relevance of studying the post-transcriptional gene regulation of miRNAs for KSHV-associated malignancies.

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.

Dataset Information

Genome-wide small RNA sequencing analysis of KSHV long-term-infected endothelial (LTC) and parental uninfected TIVE cells [miRNA-seq]

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets