Identification of VRK1 as a New Neuroblastoma Tumor Progression Marker Regulating Cell Proliferation

Abstract

Neuroblastoma (NB) is one of the most common pediatric cancers and presents a poor survival rate in affected children. Current pretreatment risk assessment relies on a few known molecular parameters, like the amplification of the oncogene MYCN. However, a better molecular knowledge about the aggressive progression of the disease is needed to provide new therapeutical targets and prognostic markers and to improve patients’ outcomes. The human protein kinase VRK1 phosphorylates various signaling molecules and transcription factors to regulate cell cycle progression and other processes in physiological and pathological situations. Using neuroblastoma tumor expression data, tissue microarrays from fresh human samples and patient-derived xenografts (PDXs), we have determined that VRK1 kinase expression stratifies patients according to tumor aggressiveness and survival, allowing the identification of patients with worse outcome among intermediate risk. VRK1 associates with cell cycle signaling pathways in NB and its downregulation abrogates cell proliferation in vitro and in vivo. Through the analysis of ChIP-seq and methylation data from NB tumors, we show that VRK1 is a MYCN gene target, however VRK1 correlates with NB aggressiveness independently of MYCN gene amplification, synergizing with the oncogene to drive NB progression. Our study also suggests that VRK1 inhibition may constitute a novel cell-cycle-targeted strategy for anticancer therapy in neuroblastoma.

Keywords

• neuroblastoma
• high-risk
• VRK1
• proliferation
• MYCN
• tumorigenesis