Abstract
Myxoma virus (MYXV), a Leporipoxvirus, is being developed as an oncolytic virotherapeutic for the treatment of a variety of human cancers. MYXV tropism for human cancer cells is largely mediated by intracellular signaling networks that regulate viral replication or innate antiviral response pathways. Thus, MYXV is fully or partially permissive for the majority of human cancer cells that harbor defects in antiviral signaling, but a minority are nonpermissive because the virus infection aborts before its completion. To identify host factors relevant for MYXV tropism in human cancer cells, we performed a small interfering RNA (siRNA) library screen targeting the 58 human DEAD-box RNA helicases in two permissive human cancer cells (HeLa and A549), one semi-permissive (786-0), and one nonpermissive cell line (PANC-1). Five host RNA helicases (DDX3X, DDX5, DHX9, DHX37, DDX52) were inhibitory for optimal replication and thus classified as anti-viral, while three other cellular RNA helicases (DHX29, DHX35, RIG-I) were identified as pro-viral or pro-cellular because knockdown consistently reduced MYXV replication and/or required metabolic functions of permissive cancer cells. These findings suggest that replication of MYXV, and likely all poxviruses, is dramatically regulated positively and negatively by multiple host DEAD-box RNA helicases.
Highlights
Myxoma virus (MYXV) is the prototypic member of the Leporipoxvirus genus of Poxviridae family of viruses, which causes myxomatosis disease in European rabbits, but is utterly non-pathogenic for all other non-leporid species
DDX3, DDX5/p68, DDX17/p72 have all been implicated in human malignancies, very few primary mutations have been identified in these RNA helicases[21,22]
In the case of MYXV, we previously identified DHX9 / RNA helicase A (RHA) as a host protein that physically interacts with the viral host range factor M029, which interacts with host cellular PKR, modulating MYXV tropism in a number of tested human cancer cells[10]
Summary
Received: 29 March 2017 Accepted: 6 November 2017 Published: xx xx xxxx in human cancer cells. In an effort to identify additional host factors that either restrict or enhance MYXV replication in human cancer cells, a genome-wide small interfering RNA (siRNA) library screen has been performed[32]. This screen has reported identification of large set of genes that can either enhance or reduce MYXV replication in human MDA-MB231 breast cancer cells[32]. We have screened a small siRNA library that targets the known cellular RNA helicases (58 genes) in human cancer and transformed cell lines of either the permissive or nonpermissive phenotype. We have identified five anti-viral and three pro-viral RNA helicases whose knockdown depletion significantly enhanced or reduced MYXV replication, respectively in the different classes of human cancer cells
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