N-Myc expression enhances the oncolytic effects of vesicular stomatitis virus in human neuroblastoma cells.
N-myc oncogene amplification is associated but not present in all cases of high-risk neuroblastoma (NB). Since oncogene expression could often modulate sensitivity to oncolytic viruses, we wanted to examine if N-myc expression status would determine virotherapy efficacy to high-risk NB. We showed that induction of exogenous N-myc in a non-N-myc-amplified cell line background (TET-21N) increased susceptibility to oncolytic vesicular stomatitis virus (mutant VSVΔM51) and alleviated the type I IFN-induced antiviral state. Cells with basal N-myc, on the other hand, were less susceptible to virus-induced oncolysis and established a robust IFN-mediated antiviral state. The same effects were also observed in NB cell lines with and without N-myc amplification. Microarray analysis showed that N-myc overexpression in TET-21N cells downregulated IFN-stimulated genes (ISGs) with known antiviral functions. Furthermore, virus infection caused significant changes in global gene expression in TET-21N cells overexpressing N-myc. Such changes involved ISGs with various functions. Therefore, the present study showed that augmented susceptibility to VSVΔM51 by N-myc at least involves downregulation of ISGs with antiviral functions and alleviation of the IFN-stimulated antiviral state. Our studies suggest the potential utility of N-myc amplification/overexpression as a predictive biomarker of virotherapy response for high-risk NB using IFN-sensitive oncolytic viruses.
Department of Oncology, Southern Alberta Cancer Research Institute, University of Calgary , Calgary, Alberta, Canada.
Juan C
JC
Corredor
Department of Oncology, Southern Alberta Cancer Research Institute, University of Calgary , Calgary, Alberta, Canada.
Nicole
N
Redding
Department of Oncology, Southern Alberta Cancer Research Institute, University of Calgary , Calgary, Alberta, Canada.
Karen
K
Bloté
Department of Oncology, Southern Alberta Cancer Research Institute, University of Calgary , Calgary, Alberta, Canada.
Stephen M
SM
Robbins
Department of Oncology, Southern Alberta Cancer Research Institute, University of Calgary , Calgary, Alberta, Canada.
Donna L
DL
Senger
Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Cancer Therapeutics, Ottawa Hospital Research Institute, University of Ottawa , Ottawa, Ontario, Canada.
John C
JC
Bell
Department of Oncology, Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada; Department of Surgery, Alberta Children's Hospital, Research Institute for Child and Maternal Health, Calgary, Alberta, Canada.
Paul
P
Beaudry