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Molecular analysis of human cancer cells infected by an oncolytic HSV-1 reveals multiple upregulated cellular genes and a role for SOCS1 in virus replication

Cancer Gene Therapy volume 15, pages 733–741 (2008)Cite this article

Abstract

Oncolytic herpes simplex viruses (oHSVs) are promising anticancer therapeutics. We sought to characterize the functional genomic response of human cancer cells to oHSV infection using G207, an oHSV previously evaluated in a phase I trial. Five human malignant peripheral nerve sheath tumor cell lines, with differing sensitivity to oHSV, were infected with G207 for 6 h. Functional genomic analysis of virus-infected cells demonstrated large clusters of downregulated cellular mRNAs and smaller clusters of those upregulated, including 21 genes commonly upregulated in all five lines. Of these, 7 are known to be HSV-1 induced and 14 represent novel virus-regulated genes. Gene ontology analysis revealed that a majority of G207-upregulated genes are involved in Janus kinase/signal transducer and activator of transcription signaling, transcriptional regulation, nucleic acid metabolism, protein synthesis and apoptosis. Ingenuity networks highlighted nodes for AP-1 subunits and interferon signaling via STAT1, suppressor of cytokine signaling-1 (SOCS1), SOCS3 and RANTES. As biological confirmation, we found that virus-mediated upregulation of SOCS1 correlated with sensitivity to G207 and that depletion of SOCS1 impaired virus replication by >10-fold. Further characterization of roles provided by oHSV-induced cellular genes during virus replication may be utilized to predict oncolytic efficacy and to provide rational strategies for designing next-generation oncolytic viruses.

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Acknowledgements

We thank MediGene Inc. for providing G207. This work was supported by the Cincinnati Children's Hospital Medical Center Division of Hematology and Oncology, by a University of Cincinnati Functional Genomics Seed Grant to YYM, and NIH grant R01-CA114004 to TPC. The authors have no conflicting financial interests.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    Y Y Mahller, W H Baird & T P Cripe

  2. Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    Y Y Mahller, W H Baird & T P Cripe

  3. Physician Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Y Y Mahller & W H Baird

  4. Graduate Program of Molecular and Developmental Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Y Y Mahller & W H Baird

  5. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    B Sakthivel & B J Aronow

  6. Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, University of Southern California, Los Angeles, CA, USA

    Y-H Hsu & R Mehrian-Shai

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  1. Y Y Mahller
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Correspondence to T P Cripe.

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Supplementary Information accompanies the paper on Cancer Gene Therapy website (http://www.nature.com/cgt)

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Mahller, Y., Sakthivel, B., Baird, W. et al. Molecular analysis of human cancer cells infected by an oncolytic HSV-1 reveals multiple upregulated cellular genes and a role for SOCS1 in virus replication. Cancer Gene Ther 15, 733–741 (2008). https://doi.org/10.1038/cgt.2008.40

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