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Hepatobiliary Malignancies
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Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis†‡
Article first published online: 11 FEB 2011
DOI: 10.1002/hep.24099
Copyright © 2010 American Association for the Study of Liver Diseases
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How to Cite
Gauglhofer, C., Sagmeister, S., Schrottmaier, W., Fischer, C., Rodgarkia-Dara, C., Mohr, T., Stättner, S., Bichler, C., Kandioler, D., Wrba, F., Schulte-Hermann, R., Holzmann, K., Grusch, M., Marian, B., Berger, W. and Grasl-Kraupp, B. (2011), Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology, 53: 854–864. doi: 10.1002/hep.24099
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Potential conflict of interest: Nothing to report.
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This study was supported by Herzfeldersche Familienstiftung and Fonds zur Förderung der Wissenschaftlichen Forschung (projects 17630-B12 and 19920-B12).
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Publication History
- Issue published online: 2 MAR 2011
- Article first published online: 11 FEB 2011
- Accepted manuscript online: 6 DEC 2010 12:37PM EST
- Manuscript Accepted: 18 NOV 2010
- Manuscript Received: 11 JUN 2010
Abstract
Fibroblast growth factors (FGFs) and their high-affinity receptors [fibroblast growth factor receptors (FGFRs)] contribute to autocrine and paracrine growth stimulation in several nonliver cancer entities. Here we report that at least one member of the FGF8 subfamily (FGF8, FGF17, and FGF18) was up-regulated in 59% of 34 human hepatocellular carcinoma (HCC) samples that we investigated. The levels of the corresponding receptors (FGFR2, FGFR3, and FGFR4) were also elevated in the great majority of the HCC cases. Overall, 82% of the HCC cases showed overexpression of at least one FGF and/or FGFR. The functional implications of the deregulated FGF/FGFR system were investigated by the simulation of an insufficient blood supply. When HCC-1.2, HepG2, or Hep3B cells were subjected to serum withdrawal or the hypoxia-mimetic drug deferoxamine mesylate, the expression of FGF8 subfamily members increased dramatically. In the serum-starved cells, the incidence of apoptosis was elevated, whereas the addition of FGF8, FGF17, or FGF18 impaired apoptosis, which was associated with phosphorylation of extracellular signal-regulated kinase 1/2 and ribosomal protein S6. In contrast, down-modulation of FGF18 by small interfering RNA (siRNA) significantly reduced the viability of the hepatocarcinoma cells. siRNA targeting FGF18 also impaired the cells' potential to form clones at a low cell density or in soft agar. With respect to the tumor microenvironment, FGF17 and FGF18 stimulated the growth of HCC-derived myofibroblasts, and FGF8, FGF17, and FGF18 induced the proliferation and tube formation of hepatic endothelial cells. Conclusion: FGF8, FGF17, and FGF18 are involved in autocrine and paracrine signaling in HCC and enhance the survival of tumor cells under stress conditions, malignant behavior, and neoangiogenesis. Thus, the FGF8 subfamily supports the development and progression of hepatocellular malignancy. (HEPATOLOGY 2011)