KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming
- Amy Hansen1,
- Stephen Henderson1,6,
- Dimitrios Lagos1,6,
- Leonid Nikitenko1,
- Eve Coulter2,
- Sinead Roberts1,
- Fiona Gratrix1,
- Karlie Plaisance3,
- Rolf Renne3,
- Mark Bower4,
- Paul Kellam5 and
- Chris Boshoff1,7
- 1Cancer Research UK Viral Oncology Group, University College London Cancer Institute, University College London, London WC1E 6BT, United Kingdom;
- 2Division of Infection and Immunity, University College London, London W1T 4JF, United Kingdom;
- 3Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida 32610, USA;
- 4Imperial College London, London SW7 2AZ, United Kingdom;
- 5Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom
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↵6 These authors contributed equally to this work.
Abstract
Kaposi sarcoma herpesvirus (KSHV) induces transcriptional reprogramming of endothelial cells. In particular, KSHV-infected lymphatic endothelial cells (LECs) show an up-regulation of genes associated with blood vessel endothelial cells (BECs). Consequently, KSHV-infected tumor cells in Kaposi sarcoma are poorly differentiated endothelial cells, expressing markers of both LECs and BECs. MicroRNAs (miRNAs) are short noncoding RNA molecules that act post-transcriptionally to negatively regulate gene expression. Here we validate expression of the KSHV-encoded miRNAs in Kaposi sarcoma lesions and demonstrate that these miRNAs contribute to viral-induced reprogramming by silencing the cellular transcription factor MAF (musculoaponeurotic fibrosarcoma oncogene homolog). MAF is expressed in LECs but not in BECs. We identify a novel role for MAF as a transcriptional repressor, preventing expression of BEC-specific genes, thereby maintaining the differentiation status of LECs. These findings demonstrate that viral miRNAs could influence the differentiation status of infected cells, and thereby contribute to KSHV-induced oncogenesis.
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Footnotes
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↵7 Corresponding author.
E-MAIL c.boshoff{at}ucl.ac.uk; FAX 44-20-7679-6817.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.553410.
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Supplemental material is available at http://www.genesdev.org.
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- Received August 18, 2009.
- Accepted November 23, 2009.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press