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World J Stem Cells. Oct 26, 2021; 13(10): 1417-1445
Published online Oct 26, 2021. doi: 10.4252/wjsc.v13.i10.1417
SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation
Milena Stevanovic, Natasa Kovacevic-Grujicic, Marija Mojsin, Milena Milivojevic, Danijela Drakulic
Milena Stevanovic, Natasa Kovacevic-Grujicic, Marija Mojsin, Milena Milivojevic, Danijela Drakulic, Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
Milena Stevanovic, Chair Biochemistry and Molecular Biology, Faculty of Biology, University of Belgrade, Belgrade 11158, Serbia
Milena Stevanovic, Department of Chemical and Biological Sciences, Serbian Academy of Sciences and Arts, Belgrade 11000, Serbia
Author contributions: All authors wrote the manuscript; Stevanovic M and Drakulic D designed the concept of the manuscript; Stevanovic M supervised and edited the manuscript; All authors contributed to the literature review; Stevanovic M, Milivojevic M and Mojsin M contributed to the preparation of the tables; All authors designed the figures; All authors contributed to the article and approved the submitted version.
Supported by Ministry of Education, Science and Technological Development of the Republic of Serbia, No. 451-03-9/2021-14/200042.
Conflict-of-interest statement: The authors declare no conflict of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Milena Stevanovic, PhD, Academic Fellow, Full Professor, Senior Research Fellow, Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade 152, Serbia. milenastevanovic@imgge.bg.ac.rs
Received: March 26, 2021
Peer-review started: March 26, 2021
First decision: July 4, 2021
Revised: July 15, 2021
Accepted: September 16, 2021
Article in press: September 16, 2021
Published online: October 26, 2021
Processing time: 213 Days and 10.1 Hours
Abstract

Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.

Keywords: Glioblastoma; SOX transcription factors; Glioma stem cells; Stemness; Differentiation

Core Tip: Despite the remarkable progress that has been made in understanding the cellular and molecular biology of gliomas, current therapeutic strategies have not yet provided a significant benefit to patients or a cure. This review highlights the key functions of SOX transcriptional factors (TFs) in glioblastoma (GBM) and glioma stem cells (GSCs). SOX TFs influence stemness, self-renewal, proliferation, differentiation, viability, migration, invasion, apoptosis, therapy resistance, sphere-forming capacity and tumorigenicity. We emphasized that fine-tuning of the SOX expression level is required to control the balance between the stemness and differentiation of GSCs, making SOX TFs promising therapeutic targets for combatting GBM.