The pan‑deacetylase inhibitor panobinostat modulates the expression of epithelial‑mesenchymal transition markers in hepatocellular carcinoma models

Di Fazio,Pietro; Montalbano,Roberta; Quint,Karl; Alinger,Beate; Kemmerling,Ralf; Kiesslich,Tobias; Ocker,Matthias; Neureiter,Daniel

doi:10.3892/ol.2012.951

The pan‑deacetylase inhibitor panobinostat modulates the expression of epithelial‑mesenchymal transition markers in hepatocellular carcinoma models

Authors:
- Pietro Di Fazio
- Roberta Montalbano
- Karl Quint
- Beate Alinger
- Ralf Kemmerling
- Tobias Kiesslich
- Matthias Ocker
- Daniel Neureiter
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Affiliations: Institute for Surgical Research, Philipps‑University Marburg, Baldingerstrasse, Marburg 35043, Germany, Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg 5020, Austria
Published online on: October 1, 2012 https://doi.org/10.3892/ol.2012.951
Pages: 127-134

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Abstract

Deacetylase inhibitors (DACis) represent a novel therapeutic option for human cancers by classically affecting proliferation or apoptosis. Since transdifferentiation and dedifferentiation play a key role in carcinogenesis, we investigated the epigenetic influence on the molecular differentiation status in human hepatocellular carcinoma (HCC) models. Markers of differentiation, including cytokeratin (Ck) 7, Ck8, Ck18, Ck19, Ck20, vimentin, sonic hedgehog homolog (SHH), smoothened (Smo), patched (Ptc), glioma‑associated oncogene homolog 1 (Gli1), CD133, octamer‑binding transcription factor 4 (Oct4) and β‑catenin, were examined in the human HCC cell lines HepG2 and Hep3B in vitro and in vivo (xenograft model) using quantitative real‑time PCR and immunohistochemistry following treatment with the pan‑DACi panobinostat (LBH589). Compared to untreated controls, treated HepG2 xenografts, and to a lesser extent cell lines, demonstrated a significant increase of differentiation markers Ck7 and Ck19 (classical cholangiocellular type) and Ck8 and Ck18 (classical HCC type), and a decreased level of dedifferentiation markers vimentin (mesenchymal) and SHH/Ptc (embryonic), paralleled with a more membranous expression of β‑catenin. These findings were dose‑dependently correlated with tumor size, necrosis rate, microvessel density and mitosis/Ki-67‑associated proliferation rate. Our results demonstrate that the differentiation status of human HCC cells is influenced by the pan‑DACi panobinostat, indicating that this treatment may influence the epithelial‑mesenchymal transition (EMT) status related to metastasis and aggressiveness.

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