Interaction of hypoxia-inducible factor-1α and Notch signaling regulates medulloblastoma precursor proliferation and fate.

摘要: Medulloblastoma (MDB) is the most common brain malignancy of childhood. It currently thought that MDB arises from aberrantly functioning stem cells in cerebellum fail to maintain proper control self-renewal. Additionally, it has been reported display higher endogenous Notch signaling activation, known promote survival and proliferation neoplastic neural inhibit their differentiation. Although interaction between hypoxia-inducible factor-1α (HIF-1α) required normal precursors an undifferentiated state, not identified MDB. Here, we investigate whether hypoxia, through HIF-1α stabilization, modulates Notch1 primary MDB-derived cells. Our results indicate precursor require hypoxic conditions for vitro expansion, whereas acute exposure 20% oxygen induces tumor cell differentiation death inhibition signaling. Importantly, stimulating activation with its ligand Dll4 under leads expansion CD133(+) nestin(+) precursors, suggesting a regulatory effect on In contrast, undergo neuronal when treated γ-secretase inhibitor, which prevents activation. These suggest by maintaining active form, preserves viability expansion.