{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T16:04:25Z","timestamp":1782403465469,"version":"3.54.5"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T00:00:00Z","timestamp":1708300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Association of Urology","award":["S-2021-0013"],"award-info":[{"award-number":["S-2021-0013"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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-1\u03b2 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-1\u03b2, 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\u2013Wallis tests, Chi-square tests or linear regression, dependent on the variable\u2019s category. Kaplan\u2013Meier and Cox proportional hazard analyses were used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Both IL-1\u03b2 and IL-1RA were significantly overexpressed in invasive BC compared to benign urothelium in both cohorts (p &lt; 0.005). IL-1\u03b2 was associated with vascular invasion (210 vs. 183, p &lt; 0.02), lymphatic invasion (210 vs. 180, &lt;0.05) and G3 cancer (192 vs. 188, &lt;0.04). The survival analysis revealed favorable RFS, CSS, and OS in the case of high IL-1\u03b2 expression (p &lt; 0.02, &lt;0.03, and &lt;0.006, respectively). Multivariate analyses revealed an independent impact of (low) IL1\u03b2 expression on RFS, CSS, and OS. The IL-1\u03b2 and IL-1\u03b2\/IL-1RA ratios were positively correlated to the AKT expression (p &lt; 0.05 and &lt;0.01, respectively). Additionally, the high expression of Ki-67 (&gt;15%) correlated with higher levels of IL-1\u03b2 (p = 0.01). The overexpression of IL-1\u03b2 and IL-1RA is frequently found in BC, with a prognostic significance observed for the IL-1\u03b2 protein expression. The observed link between the IL-1\u03b2\/IL-1RA axis and AKT signaling may indicate possible autophagy activation processes besides the known tumor-promoting effects of AKT.<\/jats:p>","DOI":"10.3390\/ijms25042447","type":"journal-article","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T11:23:57Z","timestamp":1708341837000},"page":"2447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Interleukin-1\u03b2\/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer\u2014An Exploratory Analysis of Clinical and Tumor Biological Significance"],"prefix":"10.3390","volume":"25","author":[{"given":"Marko","family":"Vukovic","sequence":"first","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"},{"name":"Department of Urology, Clinical Center of Montenegro, University of Montenegro, 81000 Podgorica, Montenegro"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge M.","family":"Chamlati","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3827-6996","authenticated-orcid":false,"given":"J\u00f6rg","family":"Hennenlotter","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilman","family":"Todenh\u00f6fer","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"L\u00fctfrenk","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Jersinovic","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5107-3523","authenticated-orcid":false,"given":"Igor","family":"Tsaur","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4207-9928","authenticated-orcid":false,"given":"Arnulf","family":"Stenzl","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6398-8701","authenticated-orcid":false,"given":"Steffen","family":"Rausch","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1002\/cac2.12158","article-title":"The role of the HIF-1\u03b1\/ALYREF\/PKM2 axis in glycolysis and tumorigenesis of bladder cancer","volume":"41","author":"Wang","year":"2021","journal-title":"Cancer Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13949","DOI":"10.1111\/jcmm.16003","article-title":"IGF2BP3 facilitates cell proliferation and tumorigenesis via modulation of JAK\/STAT signalling pathway in human bladder cancer","volume":"24","author":"Huang","year":"2020","journal-title":"J. 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