摘要

The Notch signaling pathway has been implicated in both developmental processes and tumorigenesis. Aberrant Notch signaling has been repeatedly demonstrated to facilitate the proliferation and survival of glioma cells by regulating downstream effectors or other signaling pathways. In glioblastoma multiforme specimens from 59 patients, Notch1 was highly expressed in tumor tissues compared with normal brain tissues, and this expression was correlated with elevated AKT phosphorylation and Snail expression. Increased nuclear localization of beta-catenin and p50 as well as enhanced IKKa/AKT interaction were also observed in glioma tissues. In U87MG cells, the activation of Notch1 by DLL4 stimulation or by the overexpression of Notch intracellular domain (NICD) resulted in AKT activation and thereby promoted beta-catenin activity and NF-B signaling. Inhibition of EGFR partially blocked the beta-catenin and NF-B signaling stimulated by Notch1 activation. Furthermore, NICD overexpression in U87MG cells led to the upregulated expression of several metastasis-associated molecules, which could be abrogated by the knockdown of either beta-catenin or p50. In U87MG and U251 cells, DLL4-induced cellular migration and invasion could be inhibited by either beta-catenin or a p50 inhibitor. Collectively, these results indicate that Notch activation could stimulate beta-catenin and NF-B signaling through AKT activation in glioma cells. Thus, Notch activation-stimulated beta-catenin and NF-?B signaling synergistically promote the migratory and invasive properties of glioma cells. (Cancer Sci 2012; 103: 181190)