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Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma
Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. The prognosis of patients is very poor, with a median overall survival of ~ 15 months after diagnosis. Cadherin‐3 (also known as P‐cadherin), a cell–cell adhesion molecule encoded by the CDH3 gene, is deregulated in s...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9297769/ https://www.ncbi.nlm.nih.gov/pubmed/34919784 http://dx.doi.org/10.1002/1878-0261.13162 |
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author | Martins, Eduarda P. Gonçalves, Céline S. Pojo, Marta Carvalho, Rita Ribeiro, Ana S. Miranda‐Gonçalves, Vera Taipa, Ricardo Pardal, Fernando Pinto, Afonso A. Custódia, Carlos Faria, Cláudia C. Baltazar, Fátima Sousa, Nuno Paredes, Joana Costa, Bruno M. |
author_facet | Martins, Eduarda P. Gonçalves, Céline S. Pojo, Marta Carvalho, Rita Ribeiro, Ana S. Miranda‐Gonçalves, Vera Taipa, Ricardo Pardal, Fernando Pinto, Afonso A. Custódia, Carlos Faria, Cláudia C. Baltazar, Fátima Sousa, Nuno Paredes, Joana Costa, Bruno M. |
author_sort | Martins, Eduarda P. |
collection | PubMed |
description | Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. The prognosis of patients is very poor, with a median overall survival of ~ 15 months after diagnosis. Cadherin‐3 (also known as P‐cadherin), a cell–cell adhesion molecule encoded by the CDH3 gene, is deregulated in several cancer types, but its relevance in GBM is unknown. In this study, we investigated the functional roles, the associated molecular signatures, and the prognostic value of CDH3/P‐cadherin in this highly malignant brain tumor. CDH3/P‐cadherin mRNA and protein levels were evaluated in human glioma samples. Knockdown and overexpression models of P‐cadherin in GBM were used to evaluate its functional role in vitro and in vivo. CDH3‐associated gene signatures were identified by enrichment analyses and correlations. The impact of CDH3 in the survival of GBM patients was assessed in independent cohorts using both univariable and multivariable models. We found that P‐cadherin protein is expressed in a subset of gliomas, with an increased percentage of positive samples in grade IV tumors. Concordantly, CDH3 mRNA levels in glioma samples from The Cancer Genome Atlas (TCGA) database are increased in high‐grade gliomas. P‐cadherin displays oncogenic functions in multiple knockdown and overexpression GBM cell models by affecting cell viability, cell cycle, cell invasion, migration, and neurosphere formation capacity. Genes that were positively correlated with CDH3 are enriched for oncogenic pathways commonly activated in GBM. In vivo, GBM cells expressing high levels of P‐cadherin generate larger subcutaneous tumors and cause shorter survival of mice in an orthotopic intracranial model. Concomitantly, high CDH3 expression is predictive of shorter overall survival of GBM patients in independent cohorts. Together, our results show that CDH3/P‐cadherin expression is associated with aggressiveness features of GBM and poor patient prognosis, suggesting that it may be a novel therapeutic target for this deadly brain tumor. |
format | Online Article Text |
id | pubmed-9297769 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92977692022-07-22 Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma Martins, Eduarda P. Gonçalves, Céline S. Pojo, Marta Carvalho, Rita Ribeiro, Ana S. Miranda‐Gonçalves, Vera Taipa, Ricardo Pardal, Fernando Pinto, Afonso A. Custódia, Carlos Faria, Cláudia C. Baltazar, Fátima Sousa, Nuno Paredes, Joana Costa, Bruno M. Mol Oncol Research Articles Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. The prognosis of patients is very poor, with a median overall survival of ~ 15 months after diagnosis. Cadherin‐3 (also known as P‐cadherin), a cell–cell adhesion molecule encoded by the CDH3 gene, is deregulated in several cancer types, but its relevance in GBM is unknown. In this study, we investigated the functional roles, the associated molecular signatures, and the prognostic value of CDH3/P‐cadherin in this highly malignant brain tumor. CDH3/P‐cadherin mRNA and protein levels were evaluated in human glioma samples. Knockdown and overexpression models of P‐cadherin in GBM were used to evaluate its functional role in vitro and in vivo. CDH3‐associated gene signatures were identified by enrichment analyses and correlations. The impact of CDH3 in the survival of GBM patients was assessed in independent cohorts using both univariable and multivariable models. We found that P‐cadherin protein is expressed in a subset of gliomas, with an increased percentage of positive samples in grade IV tumors. Concordantly, CDH3 mRNA levels in glioma samples from The Cancer Genome Atlas (TCGA) database are increased in high‐grade gliomas. P‐cadherin displays oncogenic functions in multiple knockdown and overexpression GBM cell models by affecting cell viability, cell cycle, cell invasion, migration, and neurosphere formation capacity. Genes that were positively correlated with CDH3 are enriched for oncogenic pathways commonly activated in GBM. In vivo, GBM cells expressing high levels of P‐cadherin generate larger subcutaneous tumors and cause shorter survival of mice in an orthotopic intracranial model. Concomitantly, high CDH3 expression is predictive of shorter overall survival of GBM patients in independent cohorts. Together, our results show that CDH3/P‐cadherin expression is associated with aggressiveness features of GBM and poor patient prognosis, suggesting that it may be a novel therapeutic target for this deadly brain tumor. John Wiley and Sons Inc. 2022-06-10 2022-07 /pmc/articles/PMC9297769/ /pubmed/34919784 http://dx.doi.org/10.1002/1878-0261.13162 Text en © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Martins, Eduarda P. Gonçalves, Céline S. Pojo, Marta Carvalho, Rita Ribeiro, Ana S. Miranda‐Gonçalves, Vera Taipa, Ricardo Pardal, Fernando Pinto, Afonso A. Custódia, Carlos Faria, Cláudia C. Baltazar, Fátima Sousa, Nuno Paredes, Joana Costa, Bruno M. Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma |
title |
Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma |
title_full |
Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma |
title_fullStr |
Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma |
title_full_unstemmed |
Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma |
title_short |
Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma |
title_sort | cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9297769/ https://www.ncbi.nlm.nih.gov/pubmed/34919784 http://dx.doi.org/10.1002/1878-0261.13162 |
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