Journal Article

Promoter-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (<i>MTAP</i>) expression in hepatocellular carcinoma

Claus Hellerbrand, Marcus Mühlbauer, Susanne Wallner, Marion Schuierer, Iris Behrmann, Frauke Bataille, Thomas Weiss, Jürgen Schölmerich and Anja-Katrin Bosserhoff

in Carcinogenesis

Volume 27, issue 1, pages 64-72
Published in print January 2005 | ISSN: 0143-3334
Published online August 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi201
Promoter-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (MTAP) expression in hepatocellular carcinoma

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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 tumour suppressor genes as p16 and p15. The aim of this study was to analyse MTAP expression in hepatocellular carcinoma (HCC) and to get an insight into the regulation and functional role of MTAP in hepatocancerogenesis. Compared with 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 with 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, whereas no effects on cell proliferation were observed in comparison with mock transfected cell clones. Furthermore, in MTAP re-expressing cells interferon (IFN)-α and IFN-γ 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 IFN sensitivity, our findings may have clinical significance for therapeutic strategies.

Keywords: HCC, hepatocellular carcinoma; IFN, interferon; ODC, ornithine decarboxylase; MTA, methylthioadenosine; MTAP, methylthioadenosine phosphorylase; PHH, primary human hepatocytes; STAT1, signal transducer and activator of transcription 1

Journal Article.  6575 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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