KSHV microRNAs mediate cellular transformation and tumorigenesis by redundantly targeting cell growth and survival pathways.

[primary effusion lymphoma]

Kaposi 's sarcoma -associated herpesvirus (KSHV ) is causally linked to several human cancers , including Kaposi 's sarcoma , primary effusion lymphoma and multicentric Castleman 's disease , malignancies commonly found in HIV-infected patients . While KSHV encodes diverse functional products , its mechanism of oncogenesis remains unknown . In this study , we determined the roles KSHV microRNAs (miRs ) in cellular transformation and tumorigenesis using a recently developed KSHV-induced cellular transformation system of primary rat mesenchymal precursor cells . A mutant with a cluster of 10 precursor miRs (pre-mi Rs ) deleted failed to transform primary cells , and instead , caused cell cycle arrest and apoptosis . Remarkably , the oncogenicity of the mutant virus was fully restored by genetic complementation with the miR cluster or several individual pre-mi Rs , which rescued cell cycle progression and inhibited apoptosis in part by redundantly targeting IκB α and the NF-κB pathway . Genomic analysis identified common targets of KSHV miRs in diverse pathways with several cancer -related pathways preferentially targeted . These works define for the first time an essential viral determinant for KSHV-induced oncogenesis and identify NF-κB as a critical pathway targeted by the viral miRs . Our results illustrate a common theme of shared functions with hierarchical order among the KSHV miRs .