Cellular Genes Targeted by KSHV MicroRNAs
Kaposi sarcoma-associated herpesvirus (KSHV) is a gamma-herpesvirus associated with Kaposi sarcoma. Recently, it was found that KSHV encodes 12 microRNAs (miRNAs) within its latency-associated region. miRNAs are small 22 nucleotide-long single-stranded RNA molecules that act to inhibit gene expression by binding to target messenger RNAs (mRNAs). Human cells express several hundred miRNAs which regulate important biological pathways such as development, proliferation, and apoptosis. Because miRNAs bind to their targets with limited base pairing, it has been difficult to find the targets. Microarray analysis of cells expressing the KSHV miRNAs revealed a set of 81 genes that were changed. Several genes are regulators of important functions such as blood vessel growth, cell proliferation, and cell death. One target, thrombospondin 1, is a potent inhibitor of blood vessel growth and is known to be down-regulated in Kaposi sarcoma tumors. We confirmed miRNA-dependent regulation for three of these genes and found that protein levels of thrombospondin 1 (THBS1) were decreased >10-fold. THBS1 has previously been reported to be down-regulated in Kaposi sarcoma lesions and has known activity as a strong tumor suppressor and anti-angiogenic factor, exerting its anti-angiogenic effect in part by activating the latent form of TGF-beta. We show that reduced THBS1 expression in the presence of viral miRNAs translates into decreased TGF-beta activity. These data suggest that KSHV-encoded miRNAs may contribute directly to pathogenesis by down-regulation of THBS1, a major regulator of cell adhesion, migration, and angiogenesis. To our knowledge, our data describe the first targets for tumorvirus-encoded miRNAs and suggest that these novel regulators may have roles in pathogenesis.
Identification of Cellular Genes Targeted by KSHV-Encoded MicroRNAs.
PLoS Pathogens 3(5): e65
[...] Cellular Genes Targeted by KSHV MicroRNAs [...]
[...] Cellular Genes Targeted by KSHV MicroRNAs [...]