Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Purpose of the study. To provide mechanistic evidence that fibroblast growth factor receptor 3 (FGFR3) and its two splice variants, FGFR3-IIIb and -IIIc, impact considerably on the malignant phenotype of hepatocellular carcinoma (HCC).</jats:p>
<jats:p>Experimental procedures. The occurrence of FGFR3 and its two isoforms was analyzed in human HCC samples by qRT-PCR and immunostaining. In hepatoma/hepatocarcinoma cell lines FGFR3-isoforms were overexpressed by lentiviral constructs or were down-modulated by siRNA or an adenoviral kinase-dead FGFR3 (kdFGFR3) construct. Cell lines were tested for anchorage-independent growth, proliferation at low-densities and their cell-cycle distribution, as well as their ability to form tumors after subcutaneous injection into the flanks of SCID-mice.</jats:p>
<jats:p>Results. Upregulated FGFR3 was found in almost 50% of HCC patients, which was often due to the enhanced expression of FGFR3-IIIb. Furthermore, patients with FGFR3-IIIb overexpression showed early tumor recurrence indicating that this isoform may be a major player in tumor progression. In hepatoma/hepatocarcinoma cells, upregulated FGFR3-IIIb or FGFR3-IIIc conferred an enhanced capability for proliferation and tumor growth. Both isoforms enhanced downstream signaling and increased the cells’ ability to grow at low densities. The tumorigenicity of cells in SCID-mice was augmented more by variant IIIb than by IIIc. This stronger impact of FGFR-IIIb on cell proliferation could also be seen in analysis of the cell cycle distribution, which was shifted to the S-phase. Conversely, siFGFR3 and kdFGFR3 affected both receptor-variants and strongly reduced clonogenic growth at low density and anchorage-independent growth. Furthermore, kdFGFR3 arrested the cells in G2/M and strongly attenuated tumor formation in vivo.</jats:p>
<jats:p>Conclusions: Upregulated FGFR3 is associated with development and progression of hepatocellular carcinoma. Accordingly, blockade of FGFR3-mediated signaling may be a promising therapeutic approach to antagonize growth and malignant behavior of HCC cells.</jats:p>
<jats:p>Citation Format: Jakob Paur, Lisa Nika, Christiane Maier, Julia Kostka, Petra Heffeter, Sonja Kappel, Daniela Kandioler, Klaus Holzmann, Brigitte Marian, Walter Berger, Michael Grusch, Bettina Grasl-Kraupp. Fibroblast growth factor receptor 3 enhances progression of hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1671. doi:10.1158/1538-7445.AM2015-1671</jats:p>