期刊
SCIENTIFIC REPORTS
卷 10, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-57076-5
关键词
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资金
- Research Foundation - Flanders (FWO) [11J8313N]
- Emmanuel van der Schueren grant ('Kom op tegen Kanker')
- Ghent University (BOF) [BOF16/PDO/043, BOF10/GOA/019]
- Research Foundation -Flanders (FWO) [12Q8319N]
- Institute for innovation by science and technology (IWT) [081373]
- Belgian Program of Interuniversity Poles of Attraction (IUAP Phase VII) [P7/03]
- Fund for Scientific Research Flanders [G053012N, G050712N, G051516N]
- ERACoSysMed project [JTC1 1500031]
- 'Stichting Villa Joep', Asset [259348]
- vzw Kinderkankerfonds, a non-profit childhood cancer foundation
Neuroblastoma is an aggressive childhood cancer arising from sympatho-adrenergic neuronal progenitors. The low survival rates for high-risk disease point to an urgent need for novel targeted therapeutic approaches. Detailed molecular characterization of the neuroblastoma genomic landscape indicates that ALK-activating mutations are present in 10% of primary tumours. Together with other mutations causing RAS/MAPK pathway activation, ALK mutations are also enriched in relapsed cases and ALK activation was shown to accelerate MYCN-driven tumour formation through hitherto unknown ALK-driven target genes. To gain further insight into how ALK contributes to neuroblastoma aggressiveness, we searched for known oncogenes in our previously reported ALK-driven gene signature. We identified ETV5, a bona fide oncogene in prostate cancer, as robustly upregulated in neuroblastoma cells harbouring ALK mutations, and show high ETV5 levels downstream of the RAS/MAPK axis. Increased ETV5 expression significantly impacted migration, invasion and colony formation in vitro, and ETV5 knockdown reduced proliferation in a murine xenograft model. We also established a gene signature associated with ETV5 knockdown that correlates with poor patient survival. Taken together, our data highlight ETV5 as an intrinsic component of oncogenic ALK-driven signalling through the MAPK axis and propose that ETV5 upregulation in neuroblastoma may contribute to tumour aggressiveness.
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