Neuronal Differentiation-Related Epigenetic Regulator ZRF1 Has Independent Prognostic Value in Neuroblastoma but Is Functionally Dispensable In Vitro.

Carlos Jiménez,Roberta Antonelli,Lucas Moreno,Josep Sánchez De Toledo,Luz Jubierre,Raquel Hladun,Soledad Gallego,Ainara Magdaleno,Aroa Soriano,Miguel F Segura,Gabriela Guillén,Laura Devis-Jauregui,David Llobet-Navas,Marc Masanas,Josep Roma,Jessica Camacho

doi:10.3390/cancers13194845

Abstract

Simple SummaryNeuroblastoma is the most common pediatric solid tumor occurring outside the brain, and it is thought to arise from cells that acquire errors during the normal process of embryonal development. Today, we know that embryonal development is regulated by epigenetics, a mechanism that determines which genes need to be expressed in each cell type and developmental step. Epigenetic errors, therefore, are considered contributory to the appearance and progression of tumors such as neuroblastoma. Here, we aimed at finding whether ZRF1, a known epigenetic regulator, could play a significant role in the aggressiveness of neuroblastoma. Our results suggest that ZRF1 does not seem to have any relevant function in neuroblastoma cells; however, the levels of this epigenetic regulator are related to the prognostic of neuroblastoma patients and could be used to predict their progression and improve the diagnosis.Neuroblastoma is a pediatric tumor of the peripheral nervous system that accounts for up to ~15% of all cancer-related deaths in children. Recently, it has become evident that epigenetic deregulation is a relevant event in pediatric tumors such as high-risk neuroblastomas, and a determinant for processes, such as cell differentiation blockade and sustained proliferation, which promote tumor progression and resistance to current therapies. Thus, a better understanding of epigenetic factors implicated in the aggressive behavior of neuroblastoma cells is crucial for the development of better treatments. In this study, we characterized the role of ZRF1, an epigenetic activator recruited to genes involved in the maintenance of the identity of neural progenitors. We combined analysis of patient sample expression datasets with loss- and gain-of-function studies on neuroblastoma cell lines. Functional analyses revealed that ZRF1 is functionally dispensable for those cellular functions related to cell differentiation, proliferation, migration, and invasion, and does not affect the cellular response to chemotherapeutic agents. However, we found that high levels of ZRF1 mRNA expression are associated to shorter overall survival of neuroblastoma patients, even when those patients with the most common molecular alterations used as prognostic factors are removed from the analyses, thereby suggesting that ZRF1 expression could be used as an independent prognostic factor in neuroblastoma.

Highlights

Neuroblastoma, a pediatric cancer of the peripheral nervous system, is one of the most common embryonal tumors outside the brain [1]
To determine whether ZRF1 is involved in the biology of neuroblastoma, we analyzed publicly available mRNA expression datasets to search for correlations between ZRF1
Receiver operating characteristic (ROC) curve analysis of a cohort of 498 patients was performed in order to assess a ZRF1 cut-off value (Youden index) that maximized the capacity for overall survival prediction (Table S4)

Summary

Introduction

Neuroblastoma, a pediatric cancer of the peripheral nervous system, is one of the most common embryonal tumors outside the brain [1]. It is thought to arise from tissues of the sympathoadrenergic system at early stages of embryonic development, from neural crest progenitors that fail to differentiate during dorsolateral migration [2]. Neuroblastoma can be classified based on the grade of morphological differentiation into distinct categories, namely neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, from less to more differentiated tumors. The pathological category can be further classified according to the degree of cellular differentiation. Neuroblastoma can be further classified into undifferentiated, poorly differentiated, and differentiating tumors (reviewed in [4]). The degree of differentiation is part of routine prognostic risk assessment. High-risk neuroblastomas, which represent up to ~60%

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Results

Conclusion