Down-regulation of methylthioadenosine phosphorylase (MTAP) induces progression of hepatocellular carcinoma via accumulation of 5'-deoxy-5'-methylthioadenosine (MTA).

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 NFκB. 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 immunohistochemical 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.

• Authors: Georgi Kirovski, Axel P Stevens, Barbara Czech, Katja Dettmer, Thomas S Weiss, Peter Wild, Arndt Hartmann, Anja K Bosserhoff, Peter J Oefner, Claus Hellerbrand
• Journal: The American journal of pathology (Am J Pathol) Vol. 178 Issue 3 Pg. 1145-52 (Mar 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21356366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Deoxyadenosines
• NF-kappa B
• RNA, Messenger
• Thionucleosides
• 5'-methylthioadenosine
• Purine-Nucleoside Phosphorylase
• 5'-methylthioadenosine phosphorylase

Topics

• Aged
• Carcinoma, Hepatocellular (enzymology, genetics, pathology)
• Cell Line, Tumor
• Deoxyadenosines (metabolism, pharmacology)
• Disease Progression
• Down-Regulation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Hepatic Stellate Cells (drug effects, enzymology)
• Humans
• Liver Neoplasms (enzymology, genetics, pathology)
• Male
• Middle Aged
• NF-kappa B (metabolism)
• Purine-Nucleoside Phosphorylase (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Thionucleosides (metabolism, pharmacology)