title: Reovirus double-stranded RNA genomes and polyI:C induce down-regulation of hypoxia-inducible factor 1α.
abstract: Reovirus has genomes consisting of 10-segmented double-stranded RNAs, and have received much attention as an oncolytic virus. A previous study reported that reovirus down-regulates hypoxia-inducible factor 1α (HIF-1α) protein levels following infection in tumor cells, which contributes to the antitumor effects of reovirus; however, the mechanism remains to be elucidated. In this study, we examined which virus component was involved in reovirus-mediated down-regulation of HIF-1α. Reovirus induced significant down-regulation of HIF-1α protein levels in not only reovirus-permissive tumor cells but also reovirus-resistant tumor cells. UV-inactivated reovirus also induced a reduction in HIF-1α protein levels. These data indicate that reovirus induces HIF-1α down-regulation independently of virus replication. Furthermore, transfection with not only reovirus genomes but also polyI:C efficiently induced HIF-1α down-regulation in a manner similar to reovirus, indicating that double-stranded reovirus RNA genomes are a key component for HIF-1α down-regulation. Reovirus-mediated HIF-1α down-regulation was inhibited when tumor cells were pretreated with inhibitors of cathepsins B and L, which play a crucial role in endo-lysosomal escape of virions to the cytoplasm. These data suggest that endo-lysosomal escape of reovirus genome into the cytoplasm is crucial for HIF-1α down-regulation; however, the retinoic acid-inducible gene-I (RIG-I) or interferon-β promoter stimulator-1 (IPS-1), which are involved in reovirus genome-induced innate immunity in the cytoplasm, did not play a crucial role in reovirus-mediated HIF-1α reduction.
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Hotani
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tachibana
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; Laboratory of Hepatic Differentiation Research, National Institute of Biomedical Innovation, Osaka, Japan; Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan; Laboratory of iPS Research, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; Laboratory of Regulatory Sciences for Oligonucleotide Therapeutics, Clinical Drug Development Unit, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan. Electronic address: sakurai@phs.osaka-u.ac.jp.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sakurai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation; D016679:Genome, Viral; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D011070:Poly I-C / Q000378:metabolism*; D012087:Reoviridae / Q000235:genetics* / Q000502:physiology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011070:Poly I-C
keywords: Cathepsin; HIF-1α; Reovirus; dsRNA; polyI:C