{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:19:05Z","timestamp":1785424745192,"version":"3.56.0"},"reference-count":20,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003083","name":"European Association of Urology","doi-asserted-by":"crossref","award":["S-2021-0013"],"award-info":[{"award-number":["S-2021-0013"]}],"id":[{"id":"10.13039\/501100003083","id-type":"DOI","asserted-by":"crossref"}]},{"award":["S-2021-0013"],"award-info":[{"award-number":["S-2021-0013"]}],"id":[{"id":"https:\/\/ror.org\/00m9mc973","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nectin-4 has emerged as a clinically relevant target in muscle-invasive bladder cancer (MIBC), primarily because of its role in antibody\u2013drug conjugate-based therapies. However, the broader biological context of Nectin-4 expression and its association with tumor-promoting signaling pathways in MIBC remain insufficiently characterized. In this single-institution study, Nectin-4 expression (H-score 0\u2013300) was assessed by immunohistochemistry in two independent MIBC cohorts. Associations between Nectin-4 expression and key markers related to growth signaling, metabolic regulation, and inflammation were analyzed alongside clinicopathological characteristics. Nectin-4 expression was significantly higher in malignant tissue than in non-malignant tissue (p = 0.0016 and p = 0.0302, respectively). Nectin-4 expression was not associated with demographic or clinicopathological parameters; however, a trend toward lower expression in more advanced disease stages was observed. Significant positive correlations were identified between Nectin-4 expression and protein kinase B (p = 0.0004), cytoplasmic (p = 0.0115) and membranous somatostatin receptor 2 (p = 0.0125), insulin receptor substrate 1 (p = 0.03), and interleukin-1 receptor antagonist (IL-1RA; p = 0.0045). In contrast, a negative correlation was observed with the IL-1\u03b2\/IL-1RA ratio (p = 0.0246). Although Nectin-4 expression was not significantly associated with cancer-specific or overall survival, a trend toward shorter relapse-free survival was observed in patients with lower Nectin-4 expression (p = 0.0531). In multivariate analysis, patient age, but not Nectin-4 expression, emerged as an independent prognostic factor. Although Nectin-4 expression does not appear to have independent prognostic value, its biological associations suggest that it reflects an integrated tumor-related signaling context. These findings support further investigation of Nectin-4 as part of rational, biology-driven therapeutic strategies in bladder cancer.<\/jats:p>","DOI":"10.3390\/ijms27135706","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T05:48:16Z","timestamp":1782366496000},"page":"5706","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nectin-4 Expression in Muscle-Invasive Bladder Cancer Is Associated with Growth-Related and Inflammatory Signaling Pathways"],"prefix":"10.3390","volume":"27","author":[{"given":"Sebastian","family":"Jersinovic","sequence":"first","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"},{"name":"Center of Modern Urology, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0265-4721","authenticated-orcid":false,"given":"Marko","family":"Vukovic","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72074 Tuebingen, Germany"},{"name":"Department of Urology, Clinical Centre of Montenegro, University of Montenegro, 81000 Podgorica, Montenegro"}],"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":"Thomas","family":"L\u00fctfrenk","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":"Clinical Practice in Urology, 72622 Nuertingen, 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"}]},{"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\/0000-0002-6398-8701","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":[[2026,6,24]]},"reference":[{"key":"ref_1","first-page":"7","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. 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