KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming.
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.
Hansen
Amy
A
Cancer Research UK Viral Oncology Group, University College London Cancer Institute, University College London, London WC1E 6BT, United Kingdom.
Henderson
Stephen
S
Lagos
Dimitrios
D
Nikitenko
Leonid
L
Coulter
Eve
E
Roberts
Sinead
S
Gratrix
Fiona
F
Plaisance
Karlie
K
Renne
Rolf
R
Bower
Mark
M
Kellam
Paul
P
Boshoff
Chris
C
D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D006367:HeLa Cells; D006566:Herpesviridae Infections / Q000503:physiopathology; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D051256:Oncogene Protein v-maf / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000503:physiopathology*
D035683:MicroRNAs; D051256:Oncogene Protein v-maf