The role of the immune system in modulating the development of virus-associated cancers is now well established. Patients with immune disorders show an increased risk for virus-associated cancer development. In humans, two viral agents highly associated with such cancers are the Epstein-Barr virus (EBV/human herpesvirus 4) and the Kaposi's sarcoma herpesvirus (KSHV/human herpesvirus 8). Both EBV and KSHV expressing multiple viral miRNAs that have been implicated in the process of oncogenic transformation.
In a previous work we showed that upon cell contact, both synthetic miRNA mimetics and viral miRNAs expressed by infected B cells can be transferred into naïve T cells and silence the expression of target transcripts in the recipient cells. In this work we investigated the intercellular transfer of the viral KSHV-miR-K12-11 (K12-11) – with homology to cellular miR-155 including the entire “seed” domain"- from BC1 cells to T cells. Using a coculture system of EBV/KSHV infected BC1 lymphoma cells, advanced cell-sorting methods, and RTqPCR we showed that the mature K12-11 miR was acquired by Jurkat cells. Next, to determine whether the transferred KSHV-miR-K12-11 is functional, we cloned the 3’UTR of BACH1 (a KSHV-miR-K12-11 target) into a luciferase expression vector and transfected Jurkat T cells with this vector. The Jurkat transfectants were co-cultured with BC1 cells. We found that following co-culture Jurkat cells showed reduced lucifarease activity compared to their control counterparts - indicating that the transferred KSHV-miR-K12-11 is indeed functional in the adopting cells.
The mechanism underlying this cell-contact-dependent process is yet unknown, however, we proved that it allows non-cell-autonomous post-transcriptional control, a process, which could be exploited by tumors or by virus-infected cells to suppress the activity of non-infected surveying lymphocytes. Better understanding of this process may lead to the development of a completely new class of anti-cancer drugs.
