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Genes & Dev. 24 (2): 195-205

Copyright © 2010 by Cold Spring Harbor Laboratory Press.

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

1 Cancer Research UK Viral Oncology Group, University College London Cancer Institute, University College London, London WC1E 6BT, United Kingdom;
2 Division of Infection and Immunity, University College London, London W1T 4JF, United Kingdom;
3 Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida 32610, USA;
4 Imperial College London, London SW7 2AZ, United Kingdom;
5 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom

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.

Key Words: MAF • viral miRNAs • Kaposi • lymphatic endothelium

Received for publication August 18, 2009. Accepted for publication November 23, 2009.

6 These authors contributed equally to this work.

7 Corresponding author.

E-MAIL c.boshoff{at}ucl.ac.uk; FAX 44-20-7679-6817.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.553410.

Supplemental material is available at http://www.genesdev.org.

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