Carcinogenesis Advance Access originally published online on August 4, 2005
Carcinogenesis 2006 27(1):64-72; doi:10.1093/carcin/bgi201
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis vol.27 no.1 © Oxford University Press 2005; all rights reserved.
Promoter-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (MTAP) expression in hepatocellular carcinoma
Department of Internal Medicine I and 1 Institute of Pathology, University of Regensburg, D-93042 Regensburg, Germany, 2 Institute of Biochemistry, RWTH-Aachen, D-52074 Aachen, Germany and 3 Department of Surgery, University of Regensburg, D-93042 Regensburg, Germany
* To whom correspondence should be addressed. Tel: +49 941 944 7104; Fax: +49 941 944 7002; Email: claus.hellerbrand{at}klinik.uni-regensburg.de
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)-
and IFN-
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H.-Y. Huang, S.-H. Li, S.-C. Yu, F.-F. Chou, C.-C. Tzeng, T.-H. Hu, Y.-H. Uen, Y.-F. Tian, Y.-H. Wang, F.-M. Fang, et al. Homozygous Deletion of MTAP Gene as a Poor Prognosticator in Gastrointestinal Stromal Tumors Clin. Cancer Res., November 15, 2009; 15(22): 6963 - 6972. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Amann, U. Maegdefrau, A. Hartmann, A. Agaimy, J. Marienhagen, T. S. Weiss, O. Stoeltzing, C. Warnecke, J. Scholmerich, P. J. Oefner, et al. GLUT1 Expression Is Increased in Hepatocellular Carcinoma and Promotes Tumorigenesis Am. J. Pathol., April 1, 2009; 174(4): 1544 - 1552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Hellerbrand, T Amann, J Schlegel, P Wild, F Bataille, T Spruss, A Hartmann, and A-K Bosserhoff The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma Gut, February 1, 2008; 57(2): 243 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Marce, O. Balague, L. Colomo, A. Martinez, S. Holler, N. Villamor, F. Bosch, G. Ott, A. Rosenwald, L. Leoni, et al. Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: implications for a potential targeted therapy. Clin. Cancer Res., June 15, 2006; 12(12): 3754 - 3761. [Abstract] [Full Text] [PDF]
|
|