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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...

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Autores principales: Stojnev, Slavica, Krstić, Miljan, Čukuranović Kokoris, Jovana, Conić, Irena, Petković, Ivan, Ilić, Sonja, Milosević-Stevanović, Jelena, Janković Veličković, Ljubinka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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.
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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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