Full text

Turn on search term navigation

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Simple Summary

Glioblastoma is the most common incurable primary brain tumor in adults, typically leading to death within 15 months of diagnosis. Although there is an ongoing debate in the scientific community about the precise cellular origin of this tumor, glioblastoma stem cells (GSCs), which are able to self-renew, yield a full tumor mass, and determine chemo- and radio-resistance, are recognized to have a pivotal role. Our research aims to understand the role of the mesenchyme homeobox 2 (MEOX2) transcription factor in GSCs where it is strongly and specifically expressed. We have found that MEOX2 is indeed important for the survival of these cells. In fact, when we reduce its expression in two different GSC lines, they undergo a massive death accompanied by the inhibition of key genes of the glycolytic metabolism, the main source of energy for these cells. Our results reveal a novel function for MEOX2 in glioblastoma and suggest a mechanism through which GSCs may survive even in unfavorable conditions.

Abstract

The most widely accepted hypothesis for the development of glioblastoma suggests that glioblastoma stem-like cells (GSCs) are crucially involved in tumor initiation and recurrence as well as in the occurrence of chemo- and radio-resistance. Mesenchyme homeobox 2 (MEOX2) is a transcription factor overexpressed in glioblastoma, whose expression is negatively correlated with patient survival. Starting from our observation that MEOX2 expression is strongly enhanced in six GSC lines, we performed shRNA-mediated knock-down experiments in two different GSC lines and found that MEOX2 depletion resulted in the inhibition of cell growth and sphere-forming ability and an increase in apoptotic cell death. By a deep transcriptome analysis, we identified a core group of genes modulated in response to MEOX2 knock-down. Among these genes, the repressed ones are largely enriched in genes involved in the hypoxic response and glycolytic pathway, two strictly related pathways that contribute to the resistance of high-grade gliomas to therapies. An in silico study of the regulatory regions of genes differentially expressed by MEOX2 knock-down revealed that they mainly consisted of GC-rich regions enriched for Sp1 and Klf4 binding motifs, two main regulators of metabolism in glioblastoma. Our results show, for the first time, the involvement of MEOX2 in the regulation of genes of GSC metabolism, which is essential for the survival and growth of these cells.

Details

Title
MEOX2 Regulates the Growth and Survival of Glioblastoma Stem Cells by Modulating Genes of the Glycolytic Pathway and Response to Hypoxia
Author
Proserpio, Carla 1   VIAFID ORCID Logo  ; Galardi, Silvia 1 ; Desimio, Maria Giovanna 2 ; Michienzi, Alessandro 1   VIAFID ORCID Logo  ; Doria, Margherita 2   VIAFID ORCID Logo  ; Minutolo, Antonella 3   VIAFID ORCID Logo  ; Matteucci, Claudia 3   VIAFID ORCID Logo  ; Ciafrè, Silvia Anna 1   VIAFID ORCID Logo 

 Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; [email protected] (C.P.); [email protected] (S.G.); [email protected] (A.M.) 
 Research Unit of Primary Immunodeficiencies, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; [email protected] (M.G.D.); [email protected] (M.D.) 
 Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; [email protected] (A.M.); [email protected] (C.M.) 
First page
2304
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2662970923
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.