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Open AccessArticle

Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer

1
Department of Pathology, Faculty of Medicine, University of Niš, 18000 Niš, Serbia
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Center for Pathology, Clinical Center Niš, 18000 Niš, Serbia
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Department of Anatomy, Faculty of Medicine, University of Niš, 18000 Niš, Serbia
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Department of Oncology, Faculty of Medicine, University of Niš, 18000 Niš, Serbia
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Clinic of Oncology, Clinical Center Niš, 18000 Niš, Serbia
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Department of Physiology, Faculty of Medicine, University of Niš, 18000 Niš, Serbia
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Department of Gynecology and Obstetrics, Faculty of Medicine, University of Niš, 18000 Niš, Serbia
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Clinic of Gynecology and Obstetrics, Clinical Center Niš, 18000 Niš, Serbia
*
Author to whom correspondence should be addressed.
Medicina 2019, 55(6), 302; https://doi.org/10.3390/medicina55060302
Received: 27 May 2019 / Revised: 12 June 2019 / Accepted: 20 June 2019 / Published: 24 June 2019
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. View Full-Text
Keywords: urothelial bladder cancer; TGF-β; Smad2; Smad4; immunohistochemistry; prognosis urothelial bladder cancer; TGF-β; Smad2; Smad4; immunohistochemistry; prognosis
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Stojnev, S.; Krstić, M.; Čukuranović Kokoris, J.; Conić, I.; Petković, I.; Ilić, S.; Milosević-Stevanović, J.; Janković Veličković, L. Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer. Medicina 2019, 55, 302.

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