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Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells

Glioblastoma multiforme (GBM) is an aggressive cancer with current therapies only marginally impacting on patient survival. Glioma stem cells (GSCs), a subpopulation of highly tumorigenic cells, are considered major contributors to glioma progression and play seminal roles in therapy resistance, imm...

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Autores principales: Talukdar, Sarmistha, Das, Swadesh K., Pradhan, Anjan K., Emdad, Luni, Shen, Xue-Ning, Windle, Jolene J., Sarkar, Devanand, Fisher, Paul B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342330/
https://www.ncbi.nlm.nih.gov/pubmed/27472461
http://dx.doi.org/10.18632/oncotarget.10851
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author Talukdar, Sarmistha
Das, Swadesh K.
Pradhan, Anjan K.
Emdad, Luni
Shen, Xue-Ning
Windle, Jolene J.
Sarkar, Devanand
Fisher, Paul B.
author_facet Talukdar, Sarmistha
Das, Swadesh K.
Pradhan, Anjan K.
Emdad, Luni
Shen, Xue-Ning
Windle, Jolene J.
Sarkar, Devanand
Fisher, Paul B.
author_sort Talukdar, Sarmistha
collection PubMed
description Glioblastoma multiforme (GBM) is an aggressive cancer with current therapies only marginally impacting on patient survival. Glioma stem cells (GSCs), a subpopulation of highly tumorigenic cells, are considered major contributors to glioma progression and play seminal roles in therapy resistance, immune evasion and increased invasion. Despite clinical relevance, effective/selective therapeutic targeting strategies for GSCs do not exist, potentially due to the lack of a definitive understanding of key regulators of GSCs. Consequently, there is a pressing need to identify therapeutic targets and novel options to effectively target this therapy-resistant cell population. The precise roles of GSCs in governing GBM development, progression and prognosis are under intense scrutiny, but key upstream regulatory genes remain speculative. MDA-9/Syntenin (SDCBP), a scaffold protein, regulates tumor pathogenesis in multiple cancers. Highly aggressive cancers like GBM express elevated levels of MDA-9 and contain increased populations of GSCs. We now uncover a unique function of MDA-9 as a facilitator and determinant of glioma stemness and survival. Mechanistically, MDA-9 regulates multiple stemness genes (Nanog, Oct4 and Sox2) through activation of STAT3. MDA-9 controls survival of GSCs by activating the NOTCH1 pathway through phospho-Src and DLL1. Once activated, cleaved NOTCH1 regulates C-Myc expression through RBPJK, thereby facilitating GSC growth and proliferation. Knockdown of MDA-9 affects the NOTCH1/C-Myc and p-STAT3/Nanog pathways causing a loss of stemness and initiation of apoptosis in GSCs. Our data uncover a previously unidentified relationship between MDA-9 and GSCs, reinforcing relevance of this gene as a potential therapeutic target in GBM.
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spelling pubmed-53423302017-03-22 Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells Talukdar, Sarmistha Das, Swadesh K. Pradhan, Anjan K. Emdad, Luni Shen, Xue-Ning Windle, Jolene J. Sarkar, Devanand Fisher, Paul B. Oncotarget Priority Research Paper Glioblastoma multiforme (GBM) is an aggressive cancer with current therapies only marginally impacting on patient survival. Glioma stem cells (GSCs), a subpopulation of highly tumorigenic cells, are considered major contributors to glioma progression and play seminal roles in therapy resistance, immune evasion and increased invasion. Despite clinical relevance, effective/selective therapeutic targeting strategies for GSCs do not exist, potentially due to the lack of a definitive understanding of key regulators of GSCs. Consequently, there is a pressing need to identify therapeutic targets and novel options to effectively target this therapy-resistant cell population. The precise roles of GSCs in governing GBM development, progression and prognosis are under intense scrutiny, but key upstream regulatory genes remain speculative. MDA-9/Syntenin (SDCBP), a scaffold protein, regulates tumor pathogenesis in multiple cancers. Highly aggressive cancers like GBM express elevated levels of MDA-9 and contain increased populations of GSCs. We now uncover a unique function of MDA-9 as a facilitator and determinant of glioma stemness and survival. Mechanistically, MDA-9 regulates multiple stemness genes (Nanog, Oct4 and Sox2) through activation of STAT3. MDA-9 controls survival of GSCs by activating the NOTCH1 pathway through phospho-Src and DLL1. Once activated, cleaved NOTCH1 regulates C-Myc expression through RBPJK, thereby facilitating GSC growth and proliferation. Knockdown of MDA-9 affects the NOTCH1/C-Myc and p-STAT3/Nanog pathways causing a loss of stemness and initiation of apoptosis in GSCs. Our data uncover a previously unidentified relationship between MDA-9 and GSCs, reinforcing relevance of this gene as a potential therapeutic target in GBM. Impact Journals LLC 2016-07-26 /pmc/articles/PMC5342330/ /pubmed/27472461 http://dx.doi.org/10.18632/oncotarget.10851 Text en Copyright: © 2016 Talukdar et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Priority Research Paper
Talukdar, Sarmistha
Das, Swadesh K.
Pradhan, Anjan K.
Emdad, Luni
Shen, Xue-Ning
Windle, Jolene J.
Sarkar, Devanand
Fisher, Paul B.
Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells
title Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells
title_full Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells
title_fullStr Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells
title_full_unstemmed Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells
title_short Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells
title_sort novel function of mda-9/syntenin (sdcbp) as a regulator of survival and stemness in glioma stem cells
topic Priority Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342330/
https://www.ncbi.nlm.nih.gov/pubmed/27472461
http://dx.doi.org/10.18632/oncotarget.10851
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