title: 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.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Georgi
authors.initials: G
authors.lastname: Kirovski
authors.forename: Axel P
authors.initials: AP
authors.lastname: Stevens
authors.forename: Barbara
authors.initials: B
authors.lastname: Czech
authors.forename: Katja
authors.initials: K
authors.lastname: Dettmer
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Anja K
authors.initials: AK
authors.lastname: Bosserhoff
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D003839:Deoxyadenosines / Q000378:metabolism* / Q000494:pharmacology; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013872:Thionucleosides / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D003839:Deoxyadenosines; D016328:NF-kappa B; D012333:RNA, Messenger; D013872:Thionucleosides; C008500:5'-methylthioadenosine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase