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KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming
Paul Kellam5,, and
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
Kaposi sarcoma herpesvirus (KSHV) induces transcriptional reprogrammingof endothelial cells. In particular, KSHV-infected lymphaticendothelial cells (LECs) show an up-regulation of genes associatedwith blood vessel endothelial cells (BECs). Consequently, KSHV-infectedtumor cells in Kaposi sarcoma are poorly differentiated endothelialcells, expressing markers of both LECs and BECs. MicroRNAs (miRNAs)are short noncoding RNA molecules that act post-transcriptionallyto negatively regulate gene expression. Here we validate expressionof the KSHV-encoded miRNAs in Kaposi sarcoma lesions and demonstratethat these miRNAs contribute to viral-induced reprogrammingby silencing the cellular transcription factor MAF (musculoaponeuroticfibrosarcoma oncogene homolog). MAF is expressed in LECs butnot in BECs. We identify a novel role for MAF as a transcriptionalrepressor, preventing expression of BEC-specific genes, therebymaintaining the differentiation status of LECs. These findingsdemonstrate that viral miRNAs could influence the differentiationstatus of infected cells, and thereby contribute to KSHV-inducedoncogenesis.
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