Z Gastroenterol 2007; 45 - A2_05
DOI: 10.1055/s-2007-967795

Regulation and function of Fibroblast Growth Factor Receptor 2IIIb (FGFR2IIIb) in hepatocancerogenesis

T Amann 1, T Spruss 2, F Bataille 3, C Liedtke 4, M Mühlbauer 1, C Trautwein 1, A Bosserhoff 3, C Hellerbrand 5
  • 1Department of Internal Medicine I, University of Regensburg, Regensburg
  • 2Institute of Pharmacy University of Regensburg, Regensburg
  • 3Institute of Pathology, University of Regensburg, Regensburg
  • 4Department of Internal Medicine III, RWTH Aachen, Aachen
  • 5Klinik und Poliklinik für Innere Medizin I der Universität Regensburg, Regensburg

The b isoform of Fibroblast Growth Factor Receptor 2 (FGFR2IIIb) is highly expressed in hepatocytes and has been shown to play an important role in liver homeostasis and regeneration. Here, we analyzed the expression and function of FGFR2IIIb in hepatocellular carcinoma (HCC).

Methods and Results: FGFR2IIIb mRNA expression was downregulated in HCC cell lines compared to primary human hepatocytes as determined by quantitative PCR. Similarly, HCC tissues from patients and animal models (c-myc and IgEGF transgenic mice) showed reduced or lost FGFR2IIIb mRNA expression compared to corresponding non-cancerous liver tissue. Immunohistochemical analysis of HCC tissues applying a newly generated polyclonal antibody that specifically recognizes the IIIb variant of the FGFR2 receptor confirmed these findings on the protein level. The 5' region of the FGFR2 gene contains a CpG island, but 5-azacytidine treatment did not affect FGFR2IIIb expression in HCC cells, excluding promotor methylation as potential cause for the FGFR2IIIb downregulation. However, cell differentiation induced by high cell density and confluence induced FGFR2IIIb mRNA and protein expression in HCC cells in vitro. To gain insight into the functional role of FGFR2IIIb downregulation in HCC, FGFR2IIIb was re-expressed in HCC cell lines by stable transfection, and the generated cell clones were analyzed in vitro and in vivo. FGFR2IIIb clones exhibited a higher basal apoptosis rate and a significantly reduced proliferation as compared to mock transfected and control cells. In accordance, FGFR2IIIb clones grew significantly slower in nude mice and Tunel staining of FGFR2IIIb tumors revealed higher apoptosis rate compared to controls.

Summary and Conclusion: Data presented indicate FGFR2IIIb as tumor suppressor of HCC and provide insight into the mechanisms of FGFR2IIIb tumor suppression. Identification and therapeutic targeting of the molecular mechanisms responsible for FGFR2IIIb suppression in HCC may be a viable method of inhibiting the progression of HCC.

FGFR2IIIb - HCC