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

Abstract: Kaposi' s sarcoma-associated herpesvirus (KSHV) is linked to several human cancers including Kaposi' s sarcoma and primary effusion lymphoma 1. Although KSHV encodes genes with oncogenic potentials 2-6,the lack of an adequate experimental system for KSHV-induced cellular transformation of primary cells has hindered the mechanistic delineation of KSHV-induced oncogenesis. We have recently demonstrated that KSHV can efficiently infect and transform primary rat mesenchymal precursor (MM) cells 7. Here, we show that regulation of cell cycle progression and apoptosis by KSHV-encoded microRNAs (miRs) is required for KSHV-induced cellular transformation and tumorigenesis. A KSHV mutant with a cluster of 10 precursor miRs (pre-miRs) deleted fails to transform MM cells, and instead causes cell cycle arrest and apoptosis. The oncogenicity of the mutant virus is restored fully by genetic complementation with the miR cluster, pre-miR-K1, -K4 or -K11, and partially by several other viral pre-miRs. KSHV miRs rescue cell cycle progression and inhibit apoptosis by directly and indirectly targeting IkBa and activating the NF-kB pathway. Inhibition of the NF-kB pathway is sufficient to induce apoptosis and causes cell cycle arrest in KSHV-transformed cells. These results demonstrate that, by subverting the IkBa and NF-kB pathway to regulate cell cycle progression and apoptosis, KSHV miRs critically contribute to KSHV-induced oncogenesis.

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