Z Gastroenterol 2011; 49 - P2_59
DOI: 10.1055/s-0030-1269576

The ubiquitin ligase SIAH-1 mediates overexpression of nucleic-acid binding protein FBP-3 and promotes HCC cell proliferation

M Malz 1, A Brauckhoff 2, A Weber 3, J Samarin 1, MO Riener 4, C Soll 5, P Schirmacher 1, K Breuhahn 1
  • 1Pathologisches Institut, Universitätsklinikum Heidelberg, Heidelberg
  • 2Institut für Pathologie, Universitätsklinik Heidelberg, Heidelberg
  • 3Department für Pathologie, Universitäts Spital Zürich, Zürich, Schweiz
  • 4Institut für Pathologie, Universitätsklinikum Erlangen, Erlangen
  • 5Klinik für Viszeral- und Transplantationschirurgie, UniversitätsSpital Zürich, Zürich, Schweiz

Background/Aims: Far upstream element (FUSE) binding protein (FBP)-1 and FBP-2 are potent regulators of hepatocellular carcinoma (HCC) cell proliferation and cell motility, respectively. In this study we aimed to analyze the expression, functional relevance, and regulation of FBP-3, another FBP family member in human hepatocarcinogenesis. Methods: Expression of FBP-3 was analyzed in normal livers, dysplastic nodules and HCCs. Functional consequences after RNAi-mediated reduction of FBP-3 on HCC cell proliferation, viability, and migration were analyzed. In order to identify potential upstream regulators of FBP-3, explorative statistical analyses using HCC-protein arrays were performed. Results: A strong nuclear overexpression of FBP-3 was observed in 74% of all analyzed human HCCs which significantly correlated with tumor dedifferentiation, tumor cell proliferation (p<0.001), and poor cumulative survival (p<0.05). FBP-3 predominantly supported proliferation but not cell migration in different HCC cell lines. Based on explorative analyses, nuclear expression of the E3-ubiquitin ligase seven in absentia homologue (SIAH)-1 significantly correlated with FBP-3 expression in dedifferentiated HCCs (p<0.01). Indeed, the knock-down of nuclear SIAH-1 as well as treatment with proteasome inhibitors drastically reduced FBP-3 transcript and protein levels. Because inhibition of SIAH-1 also reduced HCC cell viability, we tested whether exogenous FBP-3 might rescue from SIAH-1-mediated effects. Indeed, vector-based overexpression of FBP-3 partially rescued HCC cells from diminished cell viability after SIAH-1 knock-down. Conclusion: FBP-3 is strongly induced in the majority of human HCCs and represents a potent inducer of HCC cell proliferation. Its accumulation is regulated by proteasome-dependent effector mechanisms comprising nuclear activity of the ubiquitin ligase SIAH-1.

Literatur:

1. Malz M, et al. Hepatology 2009; 50: 1130-11392. Singer S, et al. Cancer Res 2009; 69: 2234-2243

E3-ubiquitin ligase - FUSE-binding protein - Hepatocellular carcinoma - tumor cell proliferation