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Published on: March 31, 2015
Integrated re-analysis of transcriptomic and proteomic datasets reveals potential mechanisms for Zika viral-based
Matt Sherwood1, Yilu Zhou1, Yi Sui1
1School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, England, SO17 1BJ, UK.
Background:
Paediatric neuroblastoma and brain tumours account for a third of all childhood cancer-related mortality. High-risk neuroblastoma is highly aggressive and survival is poor despite intensive multi-modal therapies with significant toxicity. Novel therapies are desperately needed. The Zika virus (ZIKV) can access the nervous system and there is growing interest in employing ZIKV as a potential therapy against paediatric nervous system tumours, including neuroblastoma.
Methods:
Here, we perform extensive data mining, integration and re-analysis of ZIKV infection datasets to highlight molecular mechanisms that may govern the oncolytic response in neuroblastoma cells. We collate infection data of multiple neuroblastoma cell lines by different ZIKV strains from a body of published literature to inform the susceptibility of neuroblastoma to the ZIKV oncolytic response. Integrating published transcriptomics, interaction proteomics, dependency factor and compound datasets we propose the involvement of multiple host systems during ZIKV infection.
Results:
Through data mining of published literature, we observed most paediatric neuroblastoma cell lines to be highly susceptible to ZIKV infection and propose the PRVABC59 ZIKV strain to be the most promising candidate for neuroblastoma oncolytic virotherapy. ZIKV induces TNF signalling, lipid metabolism, the Unfolded Protein Response (UPR), and downregulates cell cycle and DNA replication processes. ZIKV infection is dependent on sterol regulatory element binding protein (SREBP)-regulated lipid metabolism and three protein complexes; V-ATPase, ER Membrane Protein Complex (EMC) and mammalian translocon. We propose ZIKV non-structural protein 4B (NS4B) as a likely mediator of ZIKVs interaction with IRE1-mediated UPR, lipid metabolism and mammalian translocon.
Conclusions:
Our work provides a significant understanding of ZIKV infection in neuroblastoma cells, which will facilitate the progression of ZIKV-based oncolytic virotherapy through pre-clinical research and clinical trials.
Insights
Zika virus (ZIKV) shows promise for treating paediatric neuroblastoma by selectively infecting and killing cancer cells. Research highlights ZIKV
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Paediatric neuroblastoma and brain tumours are leading causes of childhood cancer mortality.
- High-risk neuroblastoma has poor survival rates despite aggressive treatments.
- Novel therapeutic strategies are urgently needed for these aggressive childhood cancers.
Purpose of the Study:
- To investigate the potential of Zika virus (ZIKV) as an oncolytic therapy against paediatric neuroblastoma.
- To identify molecular mechanisms underlying ZIKV's oncolytic activity in neuroblastoma cells.
- To evaluate the susceptibility of neuroblastoma cell lines to ZIKV infection.
Main Methods:
- Extensive data mining and re-analysis of published ZIKV infection datasets.
- Collation of infection data from multiple neuroblastoma cell lines and ZIKV strains.
- Integration of transcriptomics, proteomics, dependency factor, and compound datasets.
Main Results:
- Most paediatric neuroblastoma cell lines are highly susceptible to ZIKV infection.
- The PRVABC59 ZIKV strain is identified as a promising candidate for oncolytic virotherapy.
- ZIKV modulates TNF signalling, lipid metabolism, and the Unfolded Protein Response (UPR), while downregulating cell cycle and DNA replication.
- ZIKV infection relies on SREBP-regulated lipid metabolism and specific protein complexes (V-ATPase, EMC, mammalian translocon).
- ZIKV non-structural protein 4B (NS4B) is proposed as a key mediator of ZIKV's interaction with host cell machinery.
Conclusions:
- This study enhances understanding of ZIKV infection in neuroblastoma cells.
- Findings facilitate the advancement of ZIKV-based oncolytic virotherapy towards clinical application.
- ZIKV represents a potential novel therapeutic avenue for paediatric nervous system tumours.
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