Transcriptomic Meta-Analysis and Functional Validation Identify a Long Non-Coding RNA Network That Governs Zika Virus Oncolysis in Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is the most aggressive primary brain malignancy with limited treatment options and poor clinical outcomes. There is growing interest in using Zika virus as a treatment for GBM due to its selectivity in finding and killing rapidly proliferating neural cells. Several studies reproducibly show that Zika can effectively kill GBM cells. We sought to uncover the molecular mechanisms driving this cytotoxic effect by performing a meta-analysis of transcriptomic studies in which Zika virus was used to kill GBM cells. We integrated four datasets from studies on GBM and added neuroblastoma (NBM) studies as an outgroup comparator. Our analysis identified a shared molecular signature of the Zika-infected GBM cell. Interestingly, GBM cells killed by the Zika virus showed dysregulation of pathways commonly implicated in proliferation and metastasis, including TNF, NF-κB, and p53 signaling. Using a hypothesis-free design, we found several long non-coding RNAs (lncRNAs) that were consistently dysregulated in Zika-infected GBMs, many of which have previously unrecognized roles in cancer cell death. Among this group, we validated four lncRNAs for a role in Zika-mediated oncolysis. Experimental testing of MELTF-AS1, TIPARP-AS1, NR2F1-AS1, and SLC9A3-AS1 in adult GBM cell lines confirmed pronounced differential gene expression. Silencing of MELTF-AS1 augmented Zika-induced cell death, while knockdown of TIPARP-AS1, NR2F1-AS1, and SLC9A3-AS1 attenuated oncolysis, identifying a novel class of pro-oncolytic lncRNAs that critically contribute to ZIKV-mediated cytotoxicity. These findings elucidate Zika’s oncolytic mechanisms, highlight novel lncRNA targets, and support further exploration of lncRNA modulation as a strategy to enhance oncolytic virotherapy for GBM and related malignancies.