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Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer
Background and objectives: Dysregulation of TGF-β signaling plays multiple roles in cancer development and progression. In the canonical TGF-β pathway, TGF-β regulates the expression of hundreds of target genes via interaction with Smads, signal transducers and transcriptional modulators. We evaluat...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630377/ https://www.ncbi.nlm.nih.gov/pubmed/31238579 http://dx.doi.org/10.3390/medicina55060302 |
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author | Stojnev, Slavica Krstić, Miljan Čukuranović Kokoris, Jovana Conić, Irena Petković, Ivan Ilić, Sonja Milosević-Stevanović, Jelena Janković Veličković, Ljubinka |
author_facet | Stojnev, Slavica Krstić, Miljan Čukuranović Kokoris, Jovana Conić, Irena Petković, Ivan Ilić, Sonja Milosević-Stevanović, Jelena Janković Veličković, Ljubinka |
author_sort | Stojnev, Slavica |
collection | PubMed |
description | Background and objectives: Dysregulation of TGF-β signaling plays multiple roles in cancer development and progression. In the canonical TGF-β pathway, TGF-β regulates the expression of hundreds of target genes via interaction with Smads, signal transducers and transcriptional modulators. We evaluated the association of TGF-β1, Smad2, and Smad4, the key components of canonical TGFβ pathway, with clinicopathologic characteristics of urothelial bladder cancer, and assessed their prognostic value in prediction of patients’ outcome. Materials and Methods: Immunohistochemical analysis of TGF-β1, Smad2, and Smad4 expression was performed on 404 urothelial bladder cancer samples, incorporated in tissue microarrays. Expression status was correlated with clinicopathological and follow-up data. The median follow-up was 61 months. Results: High expression of TGF-β1, Smad2, and Smad4 was detected in 68.1%, 31.7% and 45.2% of the tumors, respectively. TGF-β1 overexpression was significantly associated with high tumor grade, and advanced pathologic stage (p < 0.001, respectively). Conversely, high Smad2 and Smad4 expression was linked to low tumor grade (p = 0,003, p = 0.048, respectively), and low tumor stage (p < 0.001, p = 0.003, respectively). Smad2 showed an inverse correlation with variant morphology and divergent differentiation of urothelial tumors (p = 0.014). High TGF-β1 correlated directly, while Smad2 and Smad4 correlated inversely to cancer-specific death (p = 0.043, p = 0.003, and p = 0.022, respectively). There was a strong relationship between Smad2 and Smad4 expression (p < 0.001). Survival analyses showed that high Smad2 and Smad4 expression was associated with longer overall survival (p = 0.003, p = 0.034, respectively), while in multivariate regression analysis TGF-β1 manifested as an independent predictor of poor outcome. Conclusions: Unraveling the complex roles and significance of TGF-β signaling in urothelial bladder cancer might have important implications for therapy of this disease. Assessment of TGF-β pathway status in patients with urothelial bladder cancer may provide useful prognostic information, and identify patients that could have the most benefit from therapy targeting TGF-β signaling cascade. |
format | Online Article Text |
id | pubmed-6630377 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-66303772019-08-19 Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer Stojnev, Slavica Krstić, Miljan Čukuranović Kokoris, Jovana Conić, Irena Petković, Ivan Ilić, Sonja Milosević-Stevanović, Jelena Janković Veličković, Ljubinka Medicina (Kaunas) Article Background and objectives: Dysregulation of TGF-β signaling plays multiple roles in cancer development and progression. In the canonical TGF-β pathway, TGF-β regulates the expression of hundreds of target genes via interaction with Smads, signal transducers and transcriptional modulators. We evaluated the association of TGF-β1, Smad2, and Smad4, the key components of canonical TGFβ pathway, with clinicopathologic characteristics of urothelial bladder cancer, and assessed their prognostic value in prediction of patients’ outcome. Materials and Methods: Immunohistochemical analysis of TGF-β1, Smad2, and Smad4 expression was performed on 404 urothelial bladder cancer samples, incorporated in tissue microarrays. Expression status was correlated with clinicopathological and follow-up data. The median follow-up was 61 months. Results: High expression of TGF-β1, Smad2, and Smad4 was detected in 68.1%, 31.7% and 45.2% of the tumors, respectively. TGF-β1 overexpression was significantly associated with high tumor grade, and advanced pathologic stage (p < 0.001, respectively). Conversely, high Smad2 and Smad4 expression was linked to low tumor grade (p = 0,003, p = 0.048, respectively), and low tumor stage (p < 0.001, p = 0.003, respectively). Smad2 showed an inverse correlation with variant morphology and divergent differentiation of urothelial tumors (p = 0.014). High TGF-β1 correlated directly, while Smad2 and Smad4 correlated inversely to cancer-specific death (p = 0.043, p = 0.003, and p = 0.022, respectively). There was a strong relationship between Smad2 and Smad4 expression (p < 0.001). Survival analyses showed that high Smad2 and Smad4 expression was associated with longer overall survival (p = 0.003, p = 0.034, respectively), while in multivariate regression analysis TGF-β1 manifested as an independent predictor of poor outcome. Conclusions: Unraveling the complex roles and significance of TGF-β signaling in urothelial bladder cancer might have important implications for therapy of this disease. Assessment of TGF-β pathway status in patients with urothelial bladder cancer may provide useful prognostic information, and identify patients that could have the most benefit from therapy targeting TGF-β signaling cascade. MDPI 2019-06-24 /pmc/articles/PMC6630377/ /pubmed/31238579 http://dx.doi.org/10.3390/medicina55060302 Text en © 2019 by the authors. 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/). |
spellingShingle | Article Stojnev, Slavica Krstić, Miljan Čukuranović Kokoris, Jovana Conić, Irena Petković, Ivan Ilić, Sonja Milosević-Stevanović, Jelena Janković Veličković, Ljubinka Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer |
title | Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer |
title_full | Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer |
title_fullStr | Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer |
title_full_unstemmed | Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer |
title_short | Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer |
title_sort | prognostic impact of canonical tgf-β signaling in urothelial bladder cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630377/ https://www.ncbi.nlm.nih.gov/pubmed/31238579 http://dx.doi.org/10.3390/medicina55060302 |
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