Kirovski, Georgi and Stevens, Axel P. and Czech, Barbara and Dettmer, Katja and Weiss, Thomas S. and Wild, Peter and Hartmann, Arndt and Bosserhoff, Anja K. and Oefner, Peter J. and Hellerbrand, Claus (2011) Down-Regulation of Methylthioadenosine Phosphorylase (MTAP) Induces Progression of Hepatocellular Carcinoma via Accumulation of 5 '-Deoxy-5 '-Methylthioadenosine (MTA). AMERICAN JOURNAL OF PATHOLOGY, 178 (3). pp. 1145-1152. ISSN 0002-9440,
Full text not available from this repository. (Request a copy)Abstract
Recently, we have shown that down-regulation of methylthioadenosine phosphorylase (MTAP) in hepatocellular carcinoma (HCC) cells enhances the invasive potential and the resistance against cytokines. Here, we aimed at investigating the molecular mechanism underlying this tumor-promoting effect and expanded the analysis to a large series of human HCC tissues. Liquid chromatography tandem mass spectrometry revealed that reduced MTAP expression resulted in higher intra- and extracellular concentrations of 5'-deoxy-5'-methylthioadenosine (MTA) in cultivated HCC cells and, concordantly, higher levels of MTA in HCC tissue. MTA induced matrix metalloproteinase (MMP) and interleukin-8 transcription in HCC cells in vitro, accompanied by enhanced proliferation and activation of the transcription factor NF kappa B. In addition, MTA secreted by HCC cells induced expression of fibroblast growth factor-2 and MMP1 in stromal myofibroblasts. In human HCC tissues, MTAP mRNA correlated inversely with MTA levels, and immuncohistochemical analysis of a tissue microarray of 140 human HCCs revealed that low mTAP protein expression correlated with advanced tumor stages. In conclusion, MTAP deficiency results in accumulation of MTA, which is associated with increased tumorigenicity. These data further indicate MTAP as a tumor suppressor in HCC, and MTA as a potential biomarker for HCC progression. (Am J Pathol 2011, 178:1145-1152; DOI: 10.1016/j.ajpath.2010.11.059)
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; ADENOSYL-L-METHIONINE; TUMOR-SUPPRESSOR; GENE-EXPRESSION; RAT HEPATOCYTES; GROWTH-FACTOR; CELLS; LIVER; 5'-METHYLTHIOADENOSINE; INHIBITION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin I Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 25 Jun 2020 07:21 |
| Last Modified: | 25 Jun 2020 07:21 |
| URI: | https://pred.uni-regensburg.de/id/eprint/21225 |
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