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Article

Interleukin-1β/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer—An Exploratory Analysis of Clinical and Tumor Biological Significance

by
Marko Vukovic
1,2,
Jorge M. Chamlati
1,
Jörg Hennenlotter
1,
Tilman Todenhöfer
1,
Thomas Lütfrenk
1,
Sebastian Jersinovic
1,
Igor Tsaur
1,
Arnulf Stenzl
1 and
Steffen Rausch
1,*
1
Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany
2
Department of Urology, Clinical Center of Montenegro, University of Montenegro, 81000 Podgorica, Montenegro
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(4), 2447; https://doi.org/10.3390/ijms25042447
Submission received: 8 January 2024 / Revised: 6 February 2024 / Accepted: 13 February 2024 / Published: 19 February 2024
(This article belongs to the Special Issue Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers, 2nd Edition)
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Abstract

Previous data indicate a role of IL-1 and IL-1RA imbalance in bladder carcinoma (BC); the inhibition of IL-1 signaling might be considered a treatment option. Objective: To assess expression patterns and the prognostic role of IL-1β and IL-1RA in invasive BC and to evaluate their interaction with AKT signaling and proliferation. The study included two independent cohorts of n = 92 and n = 102 patients who underwent a radical cystectomy for BC. Specimen from BC and benign urothelium (n = 22 and n = 39) were processed to a tissue microarray and immunohistochemically stained for IL-1β, IL-1RA, AKT, and Ki-67. Expression scores were correlated to clinical variables and Ki-67 and AKT expression. An association with outcome was assessed using Wilcoxon Kruskal–Wallis tests, Chi-square tests or linear regression, dependent on the variable’s category. Kaplan–Meier and Cox proportional hazard analyses were used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Both IL-1β and IL-1RA were significantly overexpressed in invasive BC compared to benign urothelium in both cohorts (p < 0.005). IL-1β was associated with vascular invasion (210 vs. 183, p < 0.02), lymphatic invasion (210 vs. 180, <0.05) and G3 cancer (192 vs. 188, <0.04). The survival analysis revealed favorable RFS, CSS, and OS in the case of high IL-1β expression (p < 0.02, <0.03, and <0.006, respectively). Multivariate analyses revealed an independent impact of (low) IL1β expression on RFS, CSS, and OS. The IL-1β and IL-1β/IL-1RA ratios were positively correlated to the AKT expression (p < 0.05 and <0.01, respectively). Additionally, the high expression of Ki-67 (>15%) correlated with higher levels of IL-1β (p = 0.01). The overexpression of IL-1β and IL-1RA is frequently found in BC, with a prognostic significance observed for the IL-1β protein expression. The observed link between the IL-1β/IL-1RA axis and AKT signaling may indicate possible autophagy activation processes besides the known tumor-promoting effects of AKT.
Keywords: urothelial cancer; metastasis; prognosis; biomarker; pathway; autophagy urothelial cancer; metastasis; prognosis; biomarker; pathway; autophagy

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MDPI and ACS Style

Vukovic, M.; Chamlati, J.M.; Hennenlotter, J.; Todenhöfer, T.; Lütfrenk, T.; Jersinovic, S.; Tsaur, I.; Stenzl, A.; Rausch, S. Interleukin-1β/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer—An Exploratory Analysis of Clinical and Tumor Biological Significance. Int. J. Mol. Sci. 2024, 25, 2447. https://doi.org/10.3390/ijms25042447

AMA Style

Vukovic M, Chamlati JM, Hennenlotter J, Todenhöfer T, Lütfrenk T, Jersinovic S, Tsaur I, Stenzl A, Rausch S. Interleukin-1β/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer—An Exploratory Analysis of Clinical and Tumor Biological Significance. International Journal of Molecular Sciences. 2024; 25(4):2447. https://doi.org/10.3390/ijms25042447

Chicago/Turabian Style

Vukovic, Marko, Jorge M. Chamlati, Jörg Hennenlotter, Tilman Todenhöfer, Thomas Lütfrenk, Sebastian Jersinovic, Igor Tsaur, Arnulf Stenzl, and Steffen Rausch. 2024. "Interleukin-1β/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer—An Exploratory Analysis of Clinical and Tumor Biological Significance" International Journal of Molecular Sciences 25, no. 4: 2447. https://doi.org/10.3390/ijms25042447

APA Style

Vukovic, M., Chamlati, J. M., Hennenlotter, J., Todenhöfer, T., Lütfrenk, T., Jersinovic, S., Tsaur, I., Stenzl, A., & Rausch, S. (2024). Interleukin-1β/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer—An Exploratory Analysis of Clinical and Tumor Biological Significance. International Journal of Molecular Sciences, 25(4), 2447. https://doi.org/10.3390/ijms25042447

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