{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T01:03:44Z","timestamp":1776474224480,"version":"3.51.2"},"reference-count":40,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Introduction: Bladder cancer is associated with a high recurrence rate, and outcomes for muscle-invasive and metastatic disease remain poor. New targeted therapies, such as the FGFR inhibitor erdafitinib, have been introduced, but the progression from non-muscle-invasive to muscle-invasive disease remains a major clinical challenge. Methods: In this study, we performed immunohistochemical staining for FGFR1-FGFR4 on surgical specimens from 192 cases of urothelial carcinoma. We also conducted various functional assays on human bladder cancer cell lines to assess protein\/gene expression, cell proliferation, migration, invasion, and colony formation. Results: FGFR2 and FGFR3 expressions were found to be significantly down-regulated in high-grade (0.014) and muscle-invasive (0.002) tumors, respectively. Functionally, the FGFR inhibitor erdafitinib suppressed cell proliferation and migration, and FGFR3 silencing also markedly reduced proliferation, migration, invasion, and colony formation in cancer cell lines. Conclusions: The down-regulation of FGFR3 in muscle-invasive bladder cancer, coupled with the inhibitory effect of its inactivation on cell growth, suggests a significant role for FGFR3 in bladder cancer progression.<\/jats:p>","DOI":"10.3390\/cancers17213588","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:14:45Z","timestamp":1762506885000},"page":"3588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Role of FGFR3 in the Progression of Bladder Cancer"],"prefix":"10.3390","volume":"17","author":[{"given":"Sahoko","family":"Ninomiya","sequence":"first","affiliation":[{"name":"Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama 232-0024, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukari","family":"Ishiguro","sequence":"additional","affiliation":[{"name":"Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama 232-0024, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8211-8835","authenticated-orcid":false,"given":"Hisashi","family":"Hasumi","sequence":"additional","affiliation":[{"name":"Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama 232-0024, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryosuke","family":"Jikuya","sequence":"additional","affiliation":[{"name":"Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama 232-0024, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1054-0779","authenticated-orcid":false,"given":"Akihito","family":"Hashizume","sequence":"additional","affiliation":[{"name":"Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama 232-0024, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanobu","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama 232-0024, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-ichi","family":"Teranishi","sequence":"additional","affiliation":[{"name":"Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama 232-0024, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7449-2015","authenticated-orcid":false,"given":"Kazuhide","family":"Makiyama","sequence":"additional","affiliation":[{"name":"Department of Urology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroji","family":"Uemura","sequence":"additional","affiliation":[{"name":"Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama 232-0024, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7610-7769","authenticated-orcid":false,"given":"Hiroshi","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Departments of Pathology & Laboratory Medicine and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Kawahara","sequence":"additional","affiliation":[{"name":"Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama 232-0024, Japan"},{"name":"Department of Urology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41389-023-00489-9","article-title":"Biological differences underlying sex and gender disparities in bladder cancer: Current synopsis and future directions","volume":"12","author":"Doshi","year":"2023","journal-title":"Oncogenesis"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.eururo.2022.06.016","article-title":"The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours","volume":"82","author":"Moch","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1056\/NEJMoa2035807","article-title":"Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma","volume":"384","author":"Powles","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_4","first-page":"507","article-title":"Bladder Cancer: Diagnosis and Treatment","volume":"96","author":"DeGeorge","year":"2017","journal-title":"Am. Fam. Physician"},{"key":"ref_5","unstructured":"Cancer Information Service NCC (2025, October 01). Japan: Cancer Statistics in Japan 2024. Foundation for Promotion of Cancer Research 2024. Available online: https:\/\/ganjoho.jp\/public\/qa_links\/report\/statistics\/2024_jp.html#toiawase."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1002\/med.21288","article-title":"FGF receptors: Cancer biology and therapeutics","volume":"34","author":"Katoh","year":"2014","journal-title":"Med. Res. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"103682","DOI":"10.1016\/j.critrevonc.2022.103682","article-title":"New emerging targets in advanced urothelial carcinoma: Is it the primetime for personalized medicine?","volume":"174","author":"Audisio","year":"2022","journal-title":"Crit. Rev. Oncol. Hematol"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100151","DOI":"10.1016\/j.modpat.2023.100151","article-title":"Frequent Telomerase Reverse Transcriptase Promoter and Fibroblast Growth Factor Receptor 3 Mutations Support the Precursor Nature of Papillary Urothelial Hyperplasia of the Urinary Bladder","volume":"36","author":"Cheng","year":"2023","journal-title":"Mod. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Brower, B., McCoy, A., Ahmad, H., Eitman, C., Bowman, I.A., Rembisz, J., and Milowsky, M.I. (2024). Managing potential adverse events during treatment with enfortumab vedotin + pembrolizumab in patients with advanced urothelial cancer. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1326715"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.4238\/2014.February.20.12","article-title":"Clinical significance of fibroblast growth factor receptor-3 mutations in bladder cancer: A systematic review and meta-analysis","volume":"13","author":"Liu","year":"2014","journal-title":"Genet. Mol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.ccr.2014.01.009","article-title":"Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy","volume":"25","author":"Choi","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Warrick, J.I., Walter, V., Yamashita, H., Shuman, L., Amponsa, V.O., Zheng, Z., Chan, W., Whitcomb, T.L., Yue, F., and Iyyanki, T. (2016). FOXA1, GATA3 and PPAR\u0263 Cooperate to Drive Luminal Subtype in Bladder Cancer: A Molecular Analysis of Established Human Cell Lines. Sci. Rep., 6.","DOI":"10.1038\/srep38531"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.eururo.2019.09.006","article-title":"A Consensus Molecular Classification of Muscle-invasive Bladder Cancer","volume":"77","author":"Kamoun","year":"2020","journal-title":"Eur. Urol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1073\/pnas.1318376111","article-title":"Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology","volume":"111","author":"Damrauer","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1056\/NEJMoa2308849","article-title":"Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma","volume":"389","author":"Loriot","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23047","DOI":"10.18632\/oncotarget.25198","article-title":"Risk-stratified surveillance protocol improves cost-effectiveness after radical nephroureterectomy in patients with upper tract urothelial carcinoma","volume":"9","author":"Momota","year":"2018","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/(SICI)1096-9896(199805)185:1<25::AID-PATH40>3.0.CO;2-R","article-title":"Rapid and prognostically valid quantification of immunohistochemical reactions by immunohistometry of the most positive tumour focus. A prospective follow-up study on breast cancer using antibodies against MIB-1, PCNA, ER, and PR","volume":"185","author":"Biesterfeld","year":"1998","journal-title":"J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1158\/1535-7163.MCT-16-0589","article-title":"Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor","volume":"16","author":"Perera","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.eururo.2017.04.015","article-title":"Prognostic Performance and Reproducibility of the 1973 and 2004\/2016 World Health Organization Grading Classification Systems in Non-muscle-invasive Bladder Cancer: A European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel Systematic Review","volume":"72","author":"Soukup","year":"2017","journal-title":"Eur. Urol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1111\/bju.16828","article-title":"Enhanced prognostic value of four-tier hybrid grading system in Ta non-muscle-invasive bladder cancer","volume":"136","author":"Ferro","year":"2025","journal-title":"BJU Int."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bizzarri, F.P., Campetella, M., Russo, P., Palermo, G., Moosavi, S.K., Rossi, F., D\u2019amico, L., Cret\u00ec, A., Gavi, F., and Panio, E. (2025). Prognostic Value of PLR, SIRI, PIV, SII, and NLR in Non-Muscle Invasive Bladder Cancer: Can Inflammatory Factors Influence Pathogenesis and Outcomes?. Cancers, 17.","DOI":"10.3390\/cancers17132189"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"148","DOI":"10.30699\/ijp.14.2.148","article-title":"Role of FGFR3 in Urothelial Carcinoma","volume":"14","author":"Akanksha","year":"2019","journal-title":"Iran. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1182\/blood-2005-01-0033","article-title":"Immunohistochemistry accurately predicts FGFR3 aberrant expression and t(4;14) in multiple myeloma","volume":"106","author":"Chang","year":"2005","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.juro.2010.09.087","article-title":"Frequency of tumor recurrence: A strong predictor of stage progression in initially diagnosed nonmuscle invasive bladder cancer","volume":"185","author":"Tanaka","year":"2011","journal-title":"J. Urol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/path.2207","article-title":"FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer","volume":"213","author":"Tomlinson","year":"2007","journal-title":"J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102530","DOI":"10.1016\/j.ctrv.2023.102530","article-title":"Role of FGFR3 in bladder cancer: Treatment landscape and future challenges","volume":"115","author":"Ascione","year":"2023","journal-title":"Cancer Treat. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kacew, A., and Sweis, R.F. (2020). FGFR3 Alterations in the Era of Immunotherapy for Urothelial Bladder Cancer. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.575258"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"414","DOI":"10.3892\/ol.2022.13534","article-title":"CD155 immunohistochemical expression in upper tract urothelial carcinoma predicts poor prognosis","volume":"24","author":"Ikeda","year":"2022","journal-title":"Oncol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1200\/JCO.21.02303","article-title":"FORT-1: Phase II\/III Study of Rogaratinib Versus Chemotherapy in Patients with Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on FGFR1\/3 mRNA Expression","volume":"41","author":"Sternberg","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_30","first-page":"326","article-title":"Clinical features of patients with MTAP-deleted bladder cancer","volume":"13","author":"Mega","year":"2023","journal-title":"Am. J. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"81","DOI":"10.30699\/ijp.2023.2012115.3180","article-title":"Do Fibroblast Growth Factor Receptor (FGFR) 2 and 3 Proteins Play a Role in Prognosis of Invasive Urothelial Bladder Carcinoma?","volume":"19","author":"Mahmoud","year":"2024","journal-title":"Iran. J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.21873\/anticanres.16357","article-title":"Nebivolol Sensitizes BT-474 Breast Cancer Cells to FGFR Inhibitors","volume":"43","author":"Kim","year":"2023","journal-title":"Anticancer Res."},{"key":"ref_33","first-page":"195","article-title":"Erdafitinib exerts the anticancer effect on urothelial carcinoma via induction of authophagy","volume":"75","author":"Jin","year":"2020","journal-title":"Pharmazie"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Cheng, T., Roth, B., Choi, W., Black, P.C., Dinney, C., and McConkey, D.J. (2013). Fibroblast growth factor receptors-1 and -3 play distinct roles in the regulation of bladder cancer growth and metastasis: Implications for therapeutic targeting. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057284"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12964-019-0486-4","article-title":"FGFR3 signaling and function in triple negative breast cancer","volume":"18","author":"Chew","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2936","DOI":"10.1245\/s10434-009-0591-5","article-title":"Inhibition of phosphatidylinositol 3-kinase\/Akt signaling suppresses tumor cell proliferation and neuroendocrine marker expression in GI carcinoid tumors","volume":"16","author":"Pitt","year":"2009","journal-title":"Ann. Surg. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Huang, G.-K., Huang, C.-C., Kang, C.-H., Cheng, Y.-T., Tsai, P.-C., Kao, Y.-H., and Chung, Y.-H. (2023). Genetic Interference of FGFR3 Impedes Invasion of Upper Tract Urothelial Carcinoma Cells by Alleviating RAS\/MAPK Signal Activity. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021776"},{"key":"ref_38","first-page":"138","article-title":"Transcriptional changes associated with in vivo growth of muscle-invasive bladder cancer cell lines in nude mice","volume":"6","author":"Ramakrishnan","year":"2018","journal-title":"Am. J. Clin. Exp. Urol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Earl, J., Rico, D., Carrillo-De-Santa-Pau, E., Rodr\u00edguez-Santiago, B., M\u00e9ndez-Pertuz, M., Auer, H., G\u00f3mez, G., Grossman, H.B., Pisano, D.G., and A Schulz, W. (2015). The UBC-40 Urothelial Bladder Cancer cell line index: A genomic resource for functional studies. BMC Genom., 16.","DOI":"10.1186\/s12864-015-1450-3"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network (2014). Comprehensive molecular characterization of urothelial bladder carcinoma. Nature, 507, 315\u2013322.","DOI":"10.1038\/nature12965"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/21\/3588\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:26:48Z","timestamp":1762507608000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/21\/3588"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,6]]},"references-count":40,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["cancers17213588"],"URL":"https:\/\/doi.org\/10.3390\/cancers17213588","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,6]]}}}