Z Gastroenterol 2011; 49 - P2_02
DOI: 10.1055/s-0030-1269519

The HDAC inhibitor Panobinostat induce differentiation and reduce de-differentiation in human hepatoma xenografts

B Alinger 1, P Di Fazio 2, K Quint 2, M Ocker 2, D Neureiter 3
  • 1Institut für Pathologie, Salzburger Landeskliniken, Salzburg, Österreich
  • 2Institut für Chirurgische Forschung, Philipps-Universität Marburg, Marburg
  • 3Institut für Pathologie, Salzburg, Österreich

Aims: Beside proliferation and apoptosis the status of trans- or de-differentiation seems to play a key role in tumor initiation, progression or metastasizing. Inhibitors of histone deacetylases (HDACi) represent a novel therapeutic option for human cancer diseases. The aim of this study is to show the possible influence of epigenetic modifications on the differentiation mechanisms of human hepatocellular carcinoma (HCC) cell line xenografts.

Materials and Methods: Human HCC cell line HepG2 was implanted subcutaneously (5×106 cells) in male NMRI mice. The pan-HDACi Panobinostat (LBH589) was applied in a dose of 2.5 and 10mg/kg KG. Specimens were characterized for proliferation and apoptosis as well as differentiation by quantitative real-time PCR, Western blotting and immunohistochemistry (cytokeratins (CK) 7, CK8/18, CK19, CK20, vimentin, Patched (PTC), Sonic Hedgehog (SHH), β-catenin, Ki-67).

Results: The investigated HCC xenografts displayed a predominant solid growth pattern. Proliferation/apoptosis were significant decreased/increased in xenografts treated with Panobinostat. Treated xenografts demonstrated a significant increase of differentiation markers (CK7/CK19: classical cholangiocellular type, CK8/18: classical HCC type) and a decreased level of markers for de-differentation (Vim: mesenchymal, SHH/PTC: embryonic) compared to untreated controls. Additionally, β-catenin showed a more cytoplasmatic expression in controls compared to a membranous expression in samples from treated mice. These findings were associated with proliferation rate (Ki-67), vasculogenesis and apoptosis/necrosis as well as with the applied dose of Panobinostat.

Conclusion: Proliferation and apoptosis as well as differentiation of human hepatoma xenografts could be influenced by the pan-HDACi Panobinostat indicating that molecular patterning of differentiation reflects activation status of tumor cells.

epigenetics - hepatocellular carcinoma - trans- and de-differentiation