{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T04:02:49Z","timestamp":1793505769267,"version":"4.5.0"},"reference-count":31,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Copper (Cu)\u2013zinc (Zn) imbalance has been implicated in colorectal cancer (CRC). Exchangeable copper (exCu), the labile circulating Cu fraction, may better reflect functionally relevant metal dysregulation than total Cu. We investigated sex-specific associations between systemic Cu\u2013Zn indices, tumor burden, and epithelial\u2013mesenchymal transition (EMT)-related tissue remodeling in CRC. We studied 152 CRC patients and 140 healthy controls. Serum Cu, Zn, and exCu were measured using validated analytical methods; circulating gonadotropins, sex steroids, and carcinoembryonic antigen were also assessed. EMT-related proteins (E-cadherin, vimentin, fibronectin, vinculin, MEMO1) were quantified by Western blot in paired tumor and adjacent mucosa. Analyses were sex-stratified and age-adjusted. CRC patients exhibited higher serum Cu and exCu and lower Zn than controls, resulting in a marked increase in the exCu:Zn ratio in both sexes. In patients, exCu:Zn was associated with tumor burden and pathological stage, with stronger associations with tumor size and pT stage in women and with metastatic status in men. Serum exCu:Zn was associated with tumor \u2212 normal differences in EMT-related proteins, particularly \u0394E-cadherin, in both sexes. Systemic Cu\u2013Zn disequilibrium, summarized by the exCu:Zn ratio, was associated with tumor burden and epithelial remodeling in CRC in a sex-specific manner, suggesting its potential as a biologically informative biomarker warranting further validation.<\/jats:p>","DOI":"10.3390\/biom16060878","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:49:42Z","timestamp":1781743782000},"page":"878","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Exchangeable Copper\u2013Zinc Ratio Links Sex Hormones, Tumor Burden, and Epithelial Remodeling in Colorectal Cancer"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5624-1140","authenticated-orcid":false,"given":"Rosanna","family":"Squitti","sequence":"first","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"},{"name":"Department of Theoretical and Applied Sciences, eCampus University, Viale Massenzio Masia, 26, 22100 Novedrate, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6532-989X","authenticated-orcid":false,"given":"Anastasia","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Roma, Italy"},{"name":"Unit of Laboratory Medicine, University Hospital Tor Vergata, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Altea","family":"Severino","sequence":"additional","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6586-0472","authenticated-orcid":false,"given":"Gianluca","family":"Rizzo","sequence":"additional","affiliation":[{"name":"UOC Chirurgia Digestiva e del Colon-Retto, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"},{"name":"Digestive Surgery Unit, Department of Translational Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1636-5766","authenticated-orcid":false,"given":"Luca Emanuele","family":"Amodio","sequence":"additional","affiliation":[{"name":"UOC Chirurgia Digestiva e del Colon-Retto, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Marzi","sequence":"additional","affiliation":[{"name":"UOC Chirurgia Digestiva e del Colon-Retto, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Vicano","sequence":"additional","affiliation":[{"name":"PhD Program in Cellular and Molecular Biology, Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0342-8961","authenticated-orcid":false,"given":"Mauro","family":"Cozzolino","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, CNR, Via Fosso del Cavaliere 100, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Lombardi","sequence":"additional","affiliation":[{"name":"Department of Theoretical and Applied Sciences, eCampus University, Viale Massenzio Masia, 26, 22100 Novedrate, Italy"},{"name":"U.P. Cytometric and Mutational Diagnostics, Vanvitelli Hospital, University of Campania \u201cLuigi Vanvitelli\u201d, 83031 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Rongioletti","sequence":"additional","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0256-3766","authenticated-orcid":false,"given":"Vincenzo","family":"Tondolo","sequence":"additional","affiliation":[{"name":"UOC Chirurgia Digestiva e del Colon-Retto, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"},{"name":"Digestive Surgery Unit, Department of Translational Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41568-021-00417-2","article-title":"Connecting copper and cancer: From transition metal signalling to metalloplasia","volume":"22","author":"Ge","year":"2022","journal-title":"Nat. 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