RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature

PLoS Pathogens

Francesco Pezzella¹  Shewit S. Tekeste¹  Coralie Viollet¹  Martin Reczko¹  Joseph M. Ziegelbauer²  Jiannis Ragoussis³  David A. Davis⁴  Robert Yarchoan⁴ 

[1] HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America;Institute of Molecular Oncology, Alexander Fleming Biomedical Sciences Research Center, Vari, Greece;Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom;The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

关键词: Hypoxia;    MicroRNAs;    Kaposi's sarcoma-associated herpesvirus;    Gene expression;    RNA sequencing;    Viral gene expression;    Gene regulation;    Glycolysis;   

DOI  :  10.1371/journal.ppat.1006143

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY