{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T16:57:36Z","timestamp":1772211456102,"version":"3.50.1"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25293095, 21H02988 and 16K15258"],"award-info":[{"award-number":["25293095, 21H02988 and 16K15258"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Aberrant activation of the Ras\/Raf\/ERK (extracellular-signal-regulated kinase)-MAPK (mitogen-activated protein kinase) pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. In the present study, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras\/Raf\/ERK-MAPK pathway, and the relation to ERK activation and Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC), and the expression was decreased in carcinoma in situ (CIS) and infiltrating urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras\/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and the expression of the cell proliferation marker Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 counters cancer progression in non-invasive papillary carcinoma possibly through inhibiting the Ras\/Raf\/ERK-MAPK pathway, but this regulatory mechanism is lost in cancers with high malignancy. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.<\/jats:p>","DOI":"10.1371\/journal.pone.0254289","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T13:31:08Z","timestamp":1637760668000},"page":"e0254289","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Expression of Spred2 in the urothelial tumorigenesis of the urinary bladder"],"prefix":"10.1371","volume":"16","author":[{"given":"Shinsuke","family":"Oda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayoshi","family":"Fujisawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Chunning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiro","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Yamaguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teizo","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5081-6089","authenticated-orcid":true,"given":"Akihiro","family":"Matsukawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,11,24]]},"reference":[{"key":"pone.0254289.ref001","doi-asserted-by":"crossref","first-page":"17022","DOI":"10.1038\/nrdp.2017.22","article-title":"Bladder cancer","volume":"3","author":"O Sanli","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"pone.0254289.ref002","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"RL Siegel","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"pone.0254289.ref003","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.urolonc.2009.04.019","article-title":"Molecular pathways of urothelial development and bladder tumorigenesis","volume":"28","author":"M Castillo-Martin","year":"2010","journal-title":"Urol Oncol"},{"key":"pone.0254289.ref004","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nrc1697","article-title":"Urothelial tumorigenesis: a tale of divergent pathways","volume":"5","author":"XR Wu","year":"2005","journal-title":"Nat Rev Cancer"},{"key":"pone.0254289.ref005","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0140-6736(09)60491-8","article-title":"Bladder cancer","volume":"374","author":"DS Kaufman","year":"2009","journal-title":"Lancet"},{"key":"pone.0254289.ref006","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.urology.2005.07.062","article-title":"Bladder cancer: epidemiology, staging and grading, and diagnosis","volume":"66","author":"Z Kirkali","year":"2005","journal-title":"Urology"},{"key":"pone.0254289.ref007","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nature12965","article-title":"Comprehensive molecular characterization of urothelial bladder carcinoma","volume":"507","author":"GARN Cancer","year":"2014","journal-title":"Nature"},{"key":"pone.0254289.ref008","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1016\/S0002-9440(10)64665-2","article-title":"Gil Diez de Medina S, Van Rhijn B et al. 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