Stevens Axel P, Spangler Barbara, Wallner Susanne, Kreutz Marina, Dettmer Katja, Oefner Peter J, Bosserhoff Anja K
Institute of Functional Genomics, University of Regensburg Medical School, Josef-Engert-Str. 9, D-93053 Regensburg, Germany.
J Cell Biochem. 2009 Feb 1;106(2):210-9. doi: 10.1002/jcb.21984.
Recent studies have shown that a loss of methylthioadenosine phosphorylase (MTAP) gene expression exerts a tumor-promoting effect, including induction of invasiveness, enhanced cell proliferation, and resistance against cytokines. To date, the molecular mechanisms underlying these effects remain unknown. Since the loss of MTAP expression resulted in induced secretion of 5'-deoxy-5'-(methylthio)adenosine (MTA), we hypothesized that MTA might modulate the observed effects. We first determined MTA levels produced by tumor cells in vitro and in situ by means of stable isotope dilution liquid chromatography tandem mass spectrometry. Subsequently, we revealed induction of matrix metalloproteinase (MMP) and growth factor gene expression in melanoma cells accompanied by enhanced invasion and vasculogenic mimicry. In addition, MTA induced the secretion of basis fibroblast growth factor (bFGF) and MMP3 from fibroblasts and the upregulation of activator protein-1 (AP-1) activity in melanoma cells and fibroblasts. In summary, we demonstrated a tumor-supporting role of MTA.
最近的研究表明，甲硫腺苷磷酸化酶（MTAP）基因表达缺失具有促肿瘤作用，包括诱导侵袭性、增强细胞增殖以及对细胞因子产生抗性。迄今为止，这些作用背后的分子机制仍不清楚。由于MTAP表达缺失导致5'-脱氧-5'-(甲硫基)腺苷（MTA）分泌增加，我们推测MTA可能调节上述所观察到的效应。我们首先通过稳定同位素稀释液相色谱串联质谱法测定肿瘤细胞在体外和原位产生的MTA水平。随后，我们发现黑色素瘤细胞中基质金属蛋白酶（MMP）和生长因子基因表达被诱导，同时侵袭和血管生成拟态增强。此外，MTA诱导成纤维细胞分泌碱性成纤维细胞生长因子（bFGF）和MMP3，并使黑色素瘤细胞和成纤维细胞中激活蛋白-1（AP-1）活性上调。总之，我们证明了MTA具有支持肿瘤生长的作用。
