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The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas
Despite the high frequency of EGFR and TP53 genetic alterations in gliomas, little is known about their crosstalk during tumor progression. Here, we described a mutually exclusive distribution between mutations in these two genes. We found that wild-type p53 gliomas are more aggressive than their mu...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017250/ https://www.ncbi.nlm.nih.gov/pubmed/31947645 http://dx.doi.org/10.3390/cancers12010208 |
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author | Segura-Collar, Berta Gargini, Ricardo Tovar-Ambel, Elena Hernández-SanMiguel, Esther Epifano, Carolina Pérez de Castro, Ignacio Hernández-Laín, Aurelio Casas-Tintó, Sergio Sánchez-Gómez, Pilar |
author_facet | Segura-Collar, Berta Gargini, Ricardo Tovar-Ambel, Elena Hernández-SanMiguel, Esther Epifano, Carolina Pérez de Castro, Ignacio Hernández-Laín, Aurelio Casas-Tintó, Sergio Sánchez-Gómez, Pilar |
author_sort | Segura-Collar, Berta |
collection | PubMed |
description | Despite the high frequency of EGFR and TP53 genetic alterations in gliomas, little is known about their crosstalk during tumor progression. Here, we described a mutually exclusive distribution between mutations in these two genes. We found that wild-type p53 gliomas are more aggressive than their mutant counterparts, probably because the former accumulate amplifications and/or mutations in EGFR and show a stronger activation of this receptor. In addition, we identified a series of genes associated with vesicular trafficking of EGFR in p53 wild-type gliomas. Among these genes, TMEM167A showed the strongest implication in overall survival in this group of tumors. In agreement with this observation, inhibition of TMEM167A expression impaired the subcutaneous and the intracranial growth of wild-type p53 gliomas, regardless of the presence of EGFR mutations. In the absence of p53 mutations, TMEM167A knockdown reduced the acidification of intracellular vesicles, affecting the autophagy process and impairing EGFR trafficking and signaling. This effect was mimicked by an inhibitor of the vacuolar ATPase. We propose that the increased aggressiveness of wild-type p53 gliomas might be due to the increase in growth factor signaling activity, which depends on the regulation of vesicular trafficking by TMEM167A. |
format | Online Article Text |
id | pubmed-7017250 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70172502020-02-28 The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas Segura-Collar, Berta Gargini, Ricardo Tovar-Ambel, Elena Hernández-SanMiguel, Esther Epifano, Carolina Pérez de Castro, Ignacio Hernández-Laín, Aurelio Casas-Tintó, Sergio Sánchez-Gómez, Pilar Cancers (Basel) Article Despite the high frequency of EGFR and TP53 genetic alterations in gliomas, little is known about their crosstalk during tumor progression. Here, we described a mutually exclusive distribution between mutations in these two genes. We found that wild-type p53 gliomas are more aggressive than their mutant counterparts, probably because the former accumulate amplifications and/or mutations in EGFR and show a stronger activation of this receptor. In addition, we identified a series of genes associated with vesicular trafficking of EGFR in p53 wild-type gliomas. Among these genes, TMEM167A showed the strongest implication in overall survival in this group of tumors. In agreement with this observation, inhibition of TMEM167A expression impaired the subcutaneous and the intracranial growth of wild-type p53 gliomas, regardless of the presence of EGFR mutations. In the absence of p53 mutations, TMEM167A knockdown reduced the acidification of intracellular vesicles, affecting the autophagy process and impairing EGFR trafficking and signaling. This effect was mimicked by an inhibitor of the vacuolar ATPase. We propose that the increased aggressiveness of wild-type p53 gliomas might be due to the increase in growth factor signaling activity, which depends on the regulation of vesicular trafficking by TMEM167A. MDPI 2020-01-14 /pmc/articles/PMC7017250/ /pubmed/31947645 http://dx.doi.org/10.3390/cancers12010208 Text en © 2020 by the authors. https://creativecommons.org/licenses/by/4.0/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 (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Segura-Collar, Berta Gargini, Ricardo Tovar-Ambel, Elena Hernández-SanMiguel, Esther Epifano, Carolina Pérez de Castro, Ignacio Hernández-Laín, Aurelio Casas-Tintó, Sergio Sánchez-Gómez, Pilar The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas |
title | The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas |
title_full | The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas |
title_fullStr | The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas |
title_full_unstemmed | The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas |
title_short | The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas |
title_sort | egfr-tmem167a-p53 axis defines the aggressiveness of gliomas |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017250/ https://www.ncbi.nlm.nih.gov/pubmed/31947645 http://dx.doi.org/10.3390/cancers12010208 |
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