Prp19 Is an Independent Prognostic Marker and Promotes Neuroblastoma Metastasis by Regulating the Hippo-YAP Signaling Pathway

Yuanxia Cai,Yeming Wu,Kai Chen,Cheng Cheng,Qianqian Cheng,Yonghu Xu,Guofeng Xu,Zhixiang Wu

doi:10.3389/fonc.2020.575366

Yuanxia Cai, Yeming Wu + Show 6 more

Open Access

https://doi.org/10.3389/fonc.2020.575366

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Abstract

Pre-mRNA processing factor 19 (Prp19) was previously reported to be involved in tumor progression. However, Prp19 expression and its functions remain elusive in neuroblastoma. Here, we aim to identify the functions and mechanisms of Prp19 in neuroblastoma. Neuroblastic tumor tissue microarrays and two independent validation data sets indicate that Prp19 is associated with high-risk markers and bone marrow metastasis and serves as a prognostic marker for worse clinical outcomes with neuroblastoma. Gain- and loss-of-expression assays reveal that Prp19 promotes invasion, migration, and epithelial–mesenchymal transition (EMT) of neuroblastoma cells in vitro. Bioinformatics analysis of RNA-seq data shows that the expressions of YAP and its downstream genes are significantly inhibited after downregulation of Prp19. Prp19 and YAP expression in metastatic lymph nodes is higher than in situ neuroblastoma tissue. Further experiments show that Prp19 regulates YAP expression and consequently affects cell invasion, migration, and EMT in neuroblastoma by pre-mRNA splicing of YAP. In conclusion, our findings provide the first evidence that Prp19 is a potential therapeutic target and prognostic biomarker for patients with neuroblastoma.

Highlights

Neuroblastoma, arising from neural crest progenitor cells of the sympathoadrenal lineage, is the most common extracranial solid tumor in children, accounting for 7.5% of all childhood cancers and 11–15% of all childhood cancer-related deaths [1, 2]
Pre-mRNA processing factor 19 (Prp19) and YAP show obvious higher expression than their paired primary tumor. These results indicate that Prp19 promotes neuroblastoma metastasis via increasing pre-mRNA splicing to upregulate the level of YAP
We first performed IHC analysis of Prp19 expression on a tissue microarray (TMA) consisting of 62 samples from patients diagnosed with neuroblastoma, including 43 NB/GNB-N and 19 GNB-I cases

Summary

Introduction

Neuroblastoma, arising from neural crest progenitor cells of the sympathoadrenal lineage, is the most common extracranial solid tumor in children, accounting for 7.5% of all childhood cancers and 11–15% of all childhood cancer-related deaths [1, 2]. The most prominent characteristic of neuroblastoma is extreme heterogeneity, which ranges from spontaneous regression in infants to metastasis and progression in older children despite intensive multimodality therapy. Children with limited lesions usually have a good prognosis, and the 5-year event-free survival (EFS) rate can reach 83% [3]. The long-term prognosis for patients with distant metastasis is poor with a 5-year EFS of 35%, which has not improved in the last decades [3,4,5]. A better understanding of the biological mechanism of metastatic neuroblastoma will likely refine treatment strategies and further improve the prognosis of metastatic patients.

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