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CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling

Glioblastoma (GBM), a highly malignant and lethal brain tumor, is characterized by diffuse invasion into the brain and chemo-radiotherapy resistance resulting in poor prognosis. In this study, we examined the involvement of the cell adhesion molecule CD146/MCAM in regulating GBM aggressiveness. Anal...

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Autores principales: Liang, Yuanke, Voshart, Daniëlle, Paridaen, Judith T. M. L., Oosterhof, Nynke, Liang, Dong, Thiruvalluvan, Arun, Zuhorn, Inge S., den Dunnen, Wilfred F. A., Zhang, Guojun, Lin, Haoyu, Barazzuol, Lara, Kruyt, Frank A. E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9256581/
https://www.ncbi.nlm.nih.gov/pubmed/35790583
http://dx.doi.org/10.1007/s00018-022-04420-0
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author Liang, Yuanke
Voshart, Daniëlle
Paridaen, Judith T. M. L.
Oosterhof, Nynke
Liang, Dong
Thiruvalluvan, Arun
Zuhorn, Inge S.
den Dunnen, Wilfred F. A.
Zhang, Guojun
Lin, Haoyu
Barazzuol, Lara
Kruyt, Frank A. E.
author_facet Liang, Yuanke
Voshart, Daniëlle
Paridaen, Judith T. M. L.
Oosterhof, Nynke
Liang, Dong
Thiruvalluvan, Arun
Zuhorn, Inge S.
den Dunnen, Wilfred F. A.
Zhang, Guojun
Lin, Haoyu
Barazzuol, Lara
Kruyt, Frank A. E.
author_sort Liang, Yuanke
collection PubMed
description Glioblastoma (GBM), a highly malignant and lethal brain tumor, is characterized by diffuse invasion into the brain and chemo-radiotherapy resistance resulting in poor prognosis. In this study, we examined the involvement of the cell adhesion molecule CD146/MCAM in regulating GBM aggressiveness. Analyses of GBM transcript expression databases revealed correlations of elevated CD146 levels with higher glioma grades, IDH-wildtype and unmethylated MGMT phenotypes, poor response to chemo-radiotherapy and worse overall survival. In a panel of GBM stem cells (GSCs) variable expression levels of CD146 were detected, which strongly increased upon adherent growth. CD146 was linked with mesenchymal transition since expression increased in TGF-ß-treated U-87MG cells. Ectopic overexpression of CD146/GFP in GG16 cells enhanced the mesenchymal phenotype and resulted in increased cell invasion. Conversely, GSC23-CD146 knockouts had decreased mesenchymal marker expression and reduced cell invasion in transwell and GBM-cortical assembloid assays. Moreover, using GSC23 xenografted zebrafish, we found that CD146 depletion resulted in more compact delineated tumor formation and reduced tumor cell dissemination. Stem cell marker expression and neurosphere formation assays showed that CD146 increased the stem cell potential of GSCs. Furthermore, CD146 mediated radioresistance by stimulating cell survival signaling through suppression of p53 expression and activation of NF-κB. Interestingly, CD146 was also identified as an inducer of the oncogenic Yes-associated protein (YAP). In conclusion, CD146 carries out various pro-tumorigenic roles in GBM involving its cell surface receptor function, which include the stimulation of mesenchymal and invasive properties, stemness, and radiotherapy resistance, thus providing an interesting target for therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04420-0.
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spelling pubmed-92565812022-07-07 CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling Liang, Yuanke Voshart, Daniëlle Paridaen, Judith T. M. L. Oosterhof, Nynke Liang, Dong Thiruvalluvan, Arun Zuhorn, Inge S. den Dunnen, Wilfred F. A. Zhang, Guojun Lin, Haoyu Barazzuol, Lara Kruyt, Frank A. E. Cell Mol Life Sci Original Article Glioblastoma (GBM), a highly malignant and lethal brain tumor, is characterized by diffuse invasion into the brain and chemo-radiotherapy resistance resulting in poor prognosis. In this study, we examined the involvement of the cell adhesion molecule CD146/MCAM in regulating GBM aggressiveness. Analyses of GBM transcript expression databases revealed correlations of elevated CD146 levels with higher glioma grades, IDH-wildtype and unmethylated MGMT phenotypes, poor response to chemo-radiotherapy and worse overall survival. In a panel of GBM stem cells (GSCs) variable expression levels of CD146 were detected, which strongly increased upon adherent growth. CD146 was linked with mesenchymal transition since expression increased in TGF-ß-treated U-87MG cells. Ectopic overexpression of CD146/GFP in GG16 cells enhanced the mesenchymal phenotype and resulted in increased cell invasion. Conversely, GSC23-CD146 knockouts had decreased mesenchymal marker expression and reduced cell invasion in transwell and GBM-cortical assembloid assays. Moreover, using GSC23 xenografted zebrafish, we found that CD146 depletion resulted in more compact delineated tumor formation and reduced tumor cell dissemination. Stem cell marker expression and neurosphere formation assays showed that CD146 increased the stem cell potential of GSCs. Furthermore, CD146 mediated radioresistance by stimulating cell survival signaling through suppression of p53 expression and activation of NF-κB. Interestingly, CD146 was also identified as an inducer of the oncogenic Yes-associated protein (YAP). In conclusion, CD146 carries out various pro-tumorigenic roles in GBM involving its cell surface receptor function, which include the stimulation of mesenchymal and invasive properties, stemness, and radiotherapy resistance, thus providing an interesting target for therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04420-0. Springer International Publishing 2022-07-05 2022 /pmc/articles/PMC9256581/ /pubmed/35790583 http://dx.doi.org/10.1007/s00018-022-04420-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Liang, Yuanke
Voshart, Daniëlle
Paridaen, Judith T. M. L.
Oosterhof, Nynke
Liang, Dong
Thiruvalluvan, Arun
Zuhorn, Inge S.
den Dunnen, Wilfred F. A.
Zhang, Guojun
Lin, Haoyu
Barazzuol, Lara
Kruyt, Frank A. E.
CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling
title CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling
title_full CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling
title_fullStr CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling
title_full_unstemmed CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling
title_short CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling
title_sort cd146 increases stemness and aggressiveness in glioblastoma and activates yap signaling
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9256581/
https://www.ncbi.nlm.nih.gov/pubmed/35790583
http://dx.doi.org/10.1007/s00018-022-04420-0
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