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Carcinogenesis Advance Access published online on August 4, 2005
Carcinogenesis, doi:10.1093/carcin/bgi201
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 7, 2005
Revised June 30, 2005
Accepted July 28, 2005

CANCER BIOLOGY

Promotor-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (MTAP) expression in hepatocellular carcinoma

Claus Hellerbrand 1*, Marcus Mühlbauer 1, Susanne Wallner 2, Marion Schuierer 2, Iris Behrmann 3, Frauke Bataille 2, Jürgen Schölmerich 1, and Anja-Katrin Bosserhoff 2

1 Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany
2 Institute of Pathology, University of Regensburg, D-93042 Regensburg, Germany
3 Institute of Biochemistry, RWTH-Aachen, D-52074 Aachen, Germany

* To whom correspondence should be addressed.
Claus Hellerbrand, E-mail: claus.hellerbrand{at}klinik.uni-regensburg.de


  Abstract

The methylthioadenosine phosphorylase (MTAP) gene is localized in the chromosomal region 9p21. Here, frequently homozygous deletions occur in several kinds of cancer associated with the loss of tumor suppressor genes as p16 and p15. The aim of this study was to analyze MTAP expression in hepatocellular carcinoma (HCC) and to get insight into regulation and functional role of MTAP in hepatocancerogenesis. Compared to primary human hepatocytes MTAP expression was markedly downregulated in three different HCC cell lines as determined by real time PCR and western blotting. This was not due to genomic losses or mutations but to promoter-hypermethylation. Reduced MTAP-expression was confirmed in vivo in HCC compared to non-cancerous liver tissue on both mRNA and protein levels. To study the functional relevance of the downregulated MTAP expression in HCC, MTAP expression was re-induced in HCC cell lines by stable transfection. In these MTAP re-expressing cell clones the invasive potential was strongly reduced, while no effects on cell proliferation were observed in comparison to mock transfected cell clones. Furthermore, in MTAP re-expressing cells interferon-alpha and interferon-gamma induced a significantly stronger inhibition of cell proliferation than in mock transfected cells. In conclusion, our results suggest a functional role of MTAP inactivation in HCC development and invasiveness. Furthermore, in the light of a recent report revealing an association between MTAP activity and interferon sensitivity (Mowen et al., Cell 2001), our findings may have clinical significance for therapeutic strategies.


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