Identification of Cellular Genes Targeted by KSHV-Encoded MicroRNAs

PLoS Pathogens

Alberto Riva¹  Mark A Samols¹  Henry V Baker¹  Ann M Maldonado²  Rebecca L Skalsky³  Rolf Renne³  M. Cecilia Lopez³ 

[1] Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, United States of America;Medical Scientist Training Program, Case Western Reserve University, Cleveland, Ohio, United States of America;University of Florida Shands Cancer Center, Gainesville, Florida, United States of America

关键词: MicroRNAs;    Gene expression;    Kaposi's sarcoma-associated herpesvirus;    HEK 293 cells;    Luciferase;    Luciferase assay;    Messenger RNA;    Microarrays;   

DOI  :  10.1371/journal.ppat.0030065

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

MicroRNAs (miRNAs) are 19 to 23 nucleotide–long RNAs that post-transcriptionally regulate gene expression. Human cells express several hundred miRNAs which regulate important biological pathways such as development, proliferation, and apoptosis. Recently, 12 miRNA genes have been identified within the genome of Kaposi sarcoma–associated herpesvirus; however, their functions are still unknown. To identify host cellular genes that may be targeted by these novel viral regulators, we performed gene expression profiling in cells stably expressing KSHV-encoded miRNAs. Data analysis revealed a set of 81 genes whose expression was significantly changed in the presence of miRNAs. While the majority of changes were below 2-fold, eight genes were down-regulated between 4- and 20-fold. 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-β. We show that reduced THBS1 expression in the presence of viral miRNAs translates into decreased TGF-β 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.

【 授权许可】

CC BY