{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:35:57Z","timestamp":1770816957608,"version":"3.50.1"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T00:00:00Z","timestamp":1444953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T00:00:00Z","timestamp":1444953600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:p>Fibroblast growth factor receptors (FGFRs) are frequently up\u2010regulated in subsets of hepatocellular carcinoma (HCC). Here, we provide mechanistic insight that FGFR3 splice variants IIIb and IIIc impact considerably on the malignant phenotype of HCC cells. The occurrence of FGFR3 variants was analyzed in human HCC samples. In hepatoma\/hepatocarcinoma cell lines, FGFR3 isoforms were overexpressed by lentiviral constructs or down\u2010modulated by small interfering RNA (siRNA; affecting FGFR3\u2010IIIb and \u2010IIIc) or an adenoviral kinase\u2010dead FGFR3\u2010IIIc construct (kdFGFR3). Elevated levels of FGFR3\u2010IIIb and\/or \u2010IIIc were found in 53% of HCC cases. FGFR3\u2010IIIb overexpression occurred significantly more often in primary tumors of large (pT2\u20104) than of small size (pT1). Furthermore, one or both isoforms were enhanced mostly in cases with early tumor infiltration and\/or recurrence at the time of surgery or follow\u2010up examinations. In hepatoma\/hepatocarcinoma cells, up\u2010regulated FGFR3\u2010IIIb conferred an enhanced capability for proliferation. Both FGFR3\u2010IIIb and FGFR3\u2010IIIc suppressed apoptotic activity, enhanced clonogenic growth, and induced disintegration of the blood\/lymph endothelium. The tumorigenicity of cells in severe combined immunodeficiency mice was augmented to a larger degree by variant IIIb than by IIIc. Conversely, siRNA targeting FGFR3 and kdFGFR3 reduced clonogenicity, anchorage\u2010independent growth, and disintegration of the blood\/lymph endothelium <jats:italic toggle=\"yes\">in vitro<\/jats:italic>. Furthermore, kdFGFR3 strongly attenuated tumor formation <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. <jats:italic toggle=\"yes\">Conclusions:<\/jats:italic> Deregulated FGFR3 variants exhibit specific effects in the malignant progression of HCC cells. Accordingly, blockade of FGFR3\u2010mediated signaling may be a promising therapeutic approach to antagonize growth and malignant behavior of HCC cells.(H<jats:sc>epatology<\/jats:sc> 2015;62:1767\u20131778)<\/jats:p>","DOI":"10.1002\/hep.28023","type":"journal-article","created":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T16:20:48Z","timestamp":1438446048000},"page":"1767-1778","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":39,"title":["Fibroblast growth factor receptor 3 isoforms: Novel therapeutic targets for hepatocellular carcinoma?"],"prefix":"10.1097","volume":"62","author":[{"given":"Jakob","family":"Paur","sequence":"first","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Nika","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christiane","family":"Maier","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Moscu\u2010Gregor","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Kostka","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Huber","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Mohr","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Heffeter","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Waltraud C.","family":"Schrottmaier","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja","family":"Kappel","sequence":"additional","affiliation":[{"name":"Department of Surgery,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Kandioler","sequence":"additional","affiliation":[{"name":"Department of Surgery,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Holzmann","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigitte","family":"Marian","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Grusch","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bettina","family":"Grasl\u2010Kraupp","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2015,10,16]]},"reference":[{"key":"hep28023-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/S0140-6736(11)61347-0","article-title":"Hepatocellular 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