Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany.
Mol Cancer. 2010 Feb 5;9:31. doi: 10.1186/1476-4598-9-31.
The human microbial pathogen Helicobacter pylori resides in the stomach of about fifty percent of the world's population and represents a risk factor for chronic gastritis, peptic ulcers and, in rare cases, gastric cancer. Alterations of the Wnt/beta-catenin signaling pathway have been described in almost every human cancer disease, due to the regulation of target genes being involved in cell cycle control, differentiation, cell migration or stem cell control. Our study aimed to elucidate the role of proximal Wnt signaling components low density lipoprotein receptor-related protein 6 (LRP6) and Dishevelled (Dvl) in the activation of beta-catenin early after infection of gastric epithelial cells with H. pylori.
Infection of gastric epithelial NCI-N87 cells with H. pylori induces rapid phosphorylation of the Wnt/beta-catenin pathway co-receptor LRP6 independent of the cytotoxin-associated gene A (CagA) or vacuolating cytotoxin A (VacA). However, bacteria lacking a functional type 4 secretion system (T4SS) failed to induce LRP6 phosphorylation. Further, we identified proteins of the Dvl family, namely Dvl2 and Dvl3, which are involved in LRP6 phosphorylation. H. pylori-induced nuclear accumulation of beta-catenin and its transcriptional activation, and expression of Wnt target genes are strongly reduced in stable knockdown cell lines deficient for LRP6, Dvl2 or Dvl3.
We analysed the H. pylori-induced activation of Wnt-signaling factors and demonstrate for the first time that the canonical Wnt-signaling proteins LRP6 and Dvl2 and Dvl3 are involved in the regulation of beta-catenin.
人类病原体幽门螺杆菌存在于世界上约一半人口的胃中，是慢性胃炎、消化性溃疡的危险因素，在极少数情况下还会导致胃癌。由于靶基因的调节参与细胞周期控制、分化、细胞迁移或干细胞控制，Wnt/β-连环蛋白信号通路的改变已在几乎每一种人类癌症疾病中得到描述。我们的研究旨在阐明低密度脂蛋白受体相关蛋白 6（LRP6）和 Dvl（Dishevelled）等近端 Wnt 信号成分在幽门螺杆菌感染胃上皮细胞后早期激活β-连环蛋白的作用。
幽门螺杆菌感染胃上皮细胞 NCI-N87 可诱导 Wnt/β-连环蛋白通路共受体 LRP6 的快速磷酸化，这一过程独立于细胞毒素相关基因 A（CagA）或空泡毒素 A（VacA）。然而，缺乏功能型 IV 型分泌系统（T4SS）的细菌不能诱导 LRP6 磷酸化。此外，我们还鉴定出 Dvl 家族的蛋白，即 Dvl2 和 Dvl3，它们参与 LRP6 的磷酸化。稳定敲低 LRP6、Dvl2 或 Dvl3 的细胞系中，幽门螺杆菌诱导的β-连环蛋白核积累及其转录激活以及 Wnt 靶基因的表达均显著降低。
我们分析了幽门螺杆菌诱导的 Wnt 信号因子的激活，并首次证明了经典 Wnt 信号蛋白 LRP6 和 Dvl2 和 Dvl3 参与了β-连环蛋白的调节。
