Z Gastroenterol 2011; 49 - P304
DOI: 10.1055/s-0031-1285575

Tumor selective miRNome modulation upon SAHA treatment in hepatocellular carcinoma

T Weiland 1, E Schwab 1, S Venturelli 1, A Berger 1, TS Weiss 2, M Bonin 3, UM Lauer 1, M Bitzer 1
  • 1Medical University Hospital Tübingen, Department of Internal Medicine I, Tübingen, Germany
  • 2Center for Liver Cell Research, University Hospital Regensburg, Regensburg, Germany
  • 3Microarray Facility Tübingen, Medical Genetics, University Hospital Tübingen, Tübingen, Germany

Epigenetic aberrations, including histone hypoacetylation, substantially contribute to initiation and progression of hepatocellular carcinoma (HCC). Newly developed drugs targeting epigenetic regulatory mechanisms, such as histone deacetylase inhibitors (HDACi), are available to reverse this contribution to the malignant phenotype of cancer cells. As a disease model in HCC e.g. the HDACi suberoylanilide hydroxamic acid (SAHA, VorinostatTM) was able to efficiently induce cell death in vitro and in vivo.

Recently, microRNAs have been recognized to play an important role in tumor biology. In HCC several studies clearly showed an important impact of deregulated microRNAs on tumor cell proliferation, differentiation and apoptosis. Interestingly, aberrant histone acetylation patterns are thought to deregulate the global microRNA expression pattern of tumor cells which might be an important factor in stabilizing the malignant phenotype. Therefore, we hyopthesized that a therapeutic application of HDACi might specifically alter the cancer-specific microRNA profile of HCC tumor cells.

The treatment of human-derived HepG2 hepatoblastoma cells and of non-malignant primary human hepatocytes (PHH) with clinically relevant concentrations of SAHA revealed a differenzial cellular response pattern on a phenotypic level with SAHA induced concentration- and time-dependent prominent caspase activation and tumor cell death. In contrast, PHH did not show substantial cytotoxicity upon SAHA treatment. Concerning the miRNA expression profile of both cell types, a differenzial regulation pattern was seen under a 24h SAHA pretreatment with a significant upregulation of 10 miRNAs in HepG2, whereas in PHH 4 different miRNAs were up and 1 miRNA was downregulated. The different contribution of these miRNAs to the SAHA-induced reaction pattern is currently investigated in further detail.

In summary, the identification of SAHA induced differenzial miRNA expression patterns may explain SAHAs tumor selective cellular toxicity and may help to further understand therapy relevant alterations in the miRNA profile of HCC tumor cells.