Abstract
Numb is an intracellular protein with multiple functions. The two prevalent isoforms, Numb p66 and Numb p72, are regulators of differentiation and proliferation in neuronal development. Additionally, Numb functions as cell fate determinant of stem cells and cancer stem cells and its abnormal expression has been described in several types of cancer. Involvement of deregulated Numb expression has been described in the malignant childhood brain tumor medulloblastoma, while Numb isoforms in these tumors and in cancer stem-like cells derived from them, have not been studied to date. Here we show that medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) express Numb p66 where its expression tampers stemness features. Furthermore, medulloblastoma samples evaluated in this study express decreased levels of Numb p66 while overexpressed Numb p72 compared with normal tissues. Our results uncover different roles for the two major Numb isoforms examined in medulloblastoma and a critical role for Numb p66 in regulating stem-like cells and NSCs maintenance.
Highlights
Medulloblastoma (MB) arises in the cerebellum and is the most common malignant pediatric brain tumor [1, 2], originating from both granule cell progenitor (GCPs) and neural stem cells [3]
Numb has a Pro-Differentiation Role in Cerebellar Neural Stem Cell (NSCs)
Numb protein level was lower at day 5 in Selective medium (SM) with respect to both bulk population and Neural Stem Cells (NSC), probably due to a selection of stem cells in medium, and its expression increased at day 30, when NSC culture was established (Figure 1A)
Summary
Medulloblastoma (MB) arises in the cerebellum and is the most common malignant pediatric brain tumor [1, 2], originating from both granule cell progenitor (GCPs) and neural stem cells [3]. SHH MBs account for roughly 27% of tumors and are characterized by aberrant activation of the Sonic hedgehog (Shh) pathway. This aberrant activation is mostly achieved by genetic loss of negative regulators (i.e., Ptch) or amplification of positive regulators (i.e., Gli2) [4,5,6]. In our previous studies we isolated and characterized cerebellar NSCs and SLCs of human and murine origin and we showed that Shh is a major driver of stemness in this context, through the transcriptional activity of the transcription factor Gli and the post-transcriptional regulation of Gli activity [8,9,10,11,12]
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