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However, the clinicopathological significance of Nectin-4 expression in UC remains controversial. To address this, we analyzed the expression and distribution of Nectin-4 in 147 upper tract UC (UTUC) and 93 bladder UC (BLCA) tissue samples using immunohistochemistry (IHC). High Nectin-4 expression was observed in cancerous regions, with both membranous and cytoplasmic staining patterns identified. Nectin-4 expression was detected in 84% of UTUC and 83% of BLCA cases and was associated with papillary morphology, low tumor grade, early pathological T stage, and a favorable prognosis. Compared with membranous staining, cytoplasmic staining was more frequently observed in advanced-stage UC. In UTUC, Nectin-4 expression correlated with UPK3 and GATA3 expression and inversely associated with PD-L1 and CK5\/6. A combined model incorporating Nectin-4, UPK3, GATA3, and PD-L1 expression demonstrated high predictive performance for the patient prognosis. In silico analyses confirmed the association of\n                    <jats:italic>NECTIN4<\/jats:italic>\n                    expression with a favorable prognosis in both UTUC and BLCA patients using the same cutoff values as the Hiroshima cohort. Bioinformatics analysis of RNA-Seq datasets revealed that the\n                    <jats:italic>NECTIN4<\/jats:italic>\n                    -high group was significantly associated with pathways such as oxidative phosphorylation, lipid metabolism, and chemical carcinogenesis, whereas the\n                    <jats:italic>NECTIN4<\/jats:italic>\n                    -low group was linked to epithelial\u2012mesenchymal transition (EMT). These findings underscore the clinical value of assessing Nectin-4 protein expression and localization through IHC, which may inform treatment strategies and surveillance protocols for UTUC and BLCA patients.\n                  <\/jats:p>","DOI":"10.1007\/s00428-025-04164-9","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T22:21:38Z","timestamp":1750976498000},"page":"1227-1242","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Nectin-4 expression in upper and lower tract urothelial carcinoma: correlation with early-stage disease and prognostic relevance"],"prefix":"10.1007","volume":"488","author":[{"given":"Go","family":"Kobayashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1525-5463","authenticated-orcid":false,"given":"Yohei","family":"Sekino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsutaro","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hikaru","family":"Nakahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuma","family":"Yukihiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Kobatake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kitano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Goto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Niitsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Hinoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Sentani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Hinata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"4164_CR1","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.eururo.2017.07.036","volume":"73","author":"M Roupr\u00eat","year":"2018","unstructured":"Roupr\u00eat M, Babjuk M, Comp\u00e9rat E, Zigeuner R, Sylvester RJ, Burger M, Cowan NC, Gontero P, Van Rhijn BWG, Mostafid AH, Palou J, Shariat SF (2018) European association of urology guidelines on upper urinary tract urothelial carcinoma update:2017. 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