Urokinase-type Plasminogen Activator Receptor (uPAR)-mediated Regulation of WNT/β-Catenin Signaling Is Enhanced in Irradiated Medulloblastoma Cells

摘要: Urokinase plasminogen activator receptor (uPAR) is known to promote invasion, migration, and metastasis in cancer cells. In this report, we showed that ionizing radiation (IR)-induced uPAR has a role WNT-β-catenin signaling mediates induction of stem cell (CSC)-like properties medulloblastoma lines UW228 D283. We observed IR induced the expression CSC markers, such as Musashi-1 CD44, activated WNT-7a-β-catenin molecules. Overexpression alone or with treatment led increased WNT-7a-β-catenin-TCF/LEF-mediated transactivation, thereby promoting stemness. contrast, shRNA specific for (pU) suppressed transactivation both vitro vivo. Quercetin, potent WNT/β-catenin inhibitor, uPAR-mediated activation, furthermore, addition recombinant human WNT-7a protein uPAR, indicating existence mutual regulatory relationship between signaling. was physically associated WNT effector molecule β-catenin on membrane, cytoplasm, nucleus IR-treated cells CSC. Most interestingly, demonstrated first time localization transcription factors (TF) their response elements. from uPAR-ChIP, TF protein, protein/DNA array analyses associates activating enhancer-binding 2α (AP2a) gene transcription. Moreover, association β-catenin·TCF/LEF complex various other involved during embryonic development indicates stemness, targeting combination significant therapeutic implications.