title: RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature.
abstract: Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases.
authors.affiliation: HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.|The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Coralie
authors.initials: C
authors.lastname: Viollet
authors.affiliation: HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Davis
authors.affiliation: HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Shewit S
authors.initials: SS
authors.lastname: Tekeste
authors.affiliation: Institute of Molecular Oncology, Alexander Fleming Biomedical Sciences Research Center, Vari, Greece.
authors.forename: Martin
authors.initials: M
authors.lastname: Reczko
authors.affiliation: HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Joseph M
authors.identifier: 0000-0001-6464-6941
authors.initials: JM
authors.lastname: Ziegelbauer
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pezzella
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Institute of Molecular Oncology, Alexander Fleming Biomedical Sciences Research Center, Vari, Greece.|McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada.|Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.affiliation: HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Robert
authors.identifier: 0000-0002-3057-1395
authors.initials: R
authors.lastname: Yarchoan
mesh_terms: D001483:Base Sequence; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D019295:Computational Biology; D042783:Endothelial Cells / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation / Q000235:genetics*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000254:growth & development*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D012514:Sarcoma, Kaposi / Q000235:genetics* / Q000821:virology; D017423:Sequence Analysis, RNA
chemical_list: C543800:MIRN210 microRNA, human; D035683:MicroRNAs