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.

中文翻译：

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N-Myc表达增强了人神经母细胞瘤细胞中水泡性口腔炎病毒的溶瘤作用。

N-myc癌基因扩增与高风险神经母细胞瘤（NB）的所有情况相关，但并不存在。由于癌基因表达通常可以调节对溶瘤病毒的敏感性，因此我们想检查N-myc表达状态是否会决定对高危NB的病毒疗法疗效。我们显示，在非N-myc扩增的细胞系背景（TET-21N）中诱导外源性N-myc增加了对溶瘤性水疱性口炎病毒（变异VSVΔM51）的敏感性，并减轻了I型IFN诱导的抗病毒状态。另一方面，具有基础N-myc的细胞对病毒诱导的溶瘤作用较不敏感，并建立了强大的IFN介导的抗病毒状态。在具有和不具有N-myc扩增的NB细胞系中也观察到相同的效果。芯片分析表明，TET-21N细胞中的N-myc过表达下调了具有已知抗病毒功能的IFN刺激基因（ISG）。此外，病毒感染导致过表达N-myc的TET-21N细胞中全局基因表达发生重大变化。此类更改涉及具有各种功能的ISG。因此，本研究表明，N-myc对VSVΔM51的敏感性增加至少涉及具有抗病毒功能的ISG的下调和减轻IFN刺激的抗病毒状态。我们的研究表明，N-myc扩增/过表达作为使用IFN敏感性溶瘤病毒对高危NB进行病毒疗法应答的预测生物标志物的潜在用途。病毒感染导致过表达N-myc的TET-21N细胞中全局基因表达发生重大变化。此类更改涉及具有各种功能的ISG。因此，本研究表明，N-myc对VSVΔM51的敏感性增加至少涉及具有抗病毒功能的ISG的下调和减轻IFN刺激的抗病毒状态。我们的研究表明，N-myc扩增/过表达作为使用IFN敏感性溶瘤病毒对高危NB进行病毒疗法应答的预测生物标志物具有潜在的实用性。病毒感染导致过表达N-myc的TET-21N细胞中全局基因表达发生重大变化。此类更改涉及具有各种功能的ISG。因此，本研究表明，N-myc对VSVΔM51的敏感性增加至少涉及具有抗病毒功能的ISG的下调和减轻IFN刺激的抗病毒状态。我们的研究表明，N-myc扩增/过表达作为使用IFN敏感性溶瘤病毒对高危NB进行病毒疗法应答的预测生物标志物具有潜在的实用性。