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Mol Ther Oncolytics. 2018 Dec 31;12:162-172. doi: 10.1016/j.omto.2018.12.012. eCollection 2019 Mar 29.

Systemically Administered Reovirus-Induced Downregulation of Hypoxia Inducible Factor-1α in Subcutaneous Tumors.

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Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Laboratory of Hepatocyte Regulation, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan.


Reovirus, which possesses a 10-segmented double-stranded RNA genome, mediates superior antitumor effects via not only virus replication in a tumor cell-specific manner but also other mechanisms distinct from virus replication. Several groups, including ours, reported the reovirus-mediated downregulation of hypoxia inducible factor-1α (HIF-1α) following infection in cultured tumor cells; however, it remained to be clarified whether reovirus downregulates the expression of HIF-1α and its target genes in tumor-bearing hosts. We found that reovirus induced significant downregulation of protein levels of HIF-1α and its target genes in the subcutaneous tumors at 120 h post-systemic administration. Expression of reovirus capsid protein σ3 was found in the pimonidazole-positive hypoxic area in the tumor. Significant levels of tumor cell apoptosis were not found in the tumors of reovirus-treated mice at this time point, suggesting that reovirus-mediated tumor cell killing did not largely contribute to the downregulation of HIF-1α protein levels in the tumors. UV-inactivated reovirus did not induce downregulation of HIF-1α expression in the tumors, indicating that virus replication was indispensable for downregulation of HIF-1α expression in the subcutaneous tumors. This study provides important information for the development of reovirus-mediated virotherapy against various types of tumors.


HIF-1α; hypoxia; oncolytic virus; reovirus; tumor microenvironment

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