Interaction of hypoxia-inducible factor-1α and Notch signaling regulates medulloblastoma precursor proliferation and fate.
Interaction of hypoxia-inducible factor-1α and Notch signaling regulates medulloblastoma precursor proliferation and fate.
复制标题
低氧诱导因子-1α和Notch信号传导的相互作用调节髓母细胞瘤的前体增殖和命运。
DOI：
10.1002/stem.518
复制
发表时间：
2010-11
期刊：
影响因子：
5.2
通讯作者：
Basso, Giuseppe
中科院分区：
文献类型：
--
作者：
Pistollato, Francesca;Rampazzo, Elena;Persano, Luca;Abbadi, Sara;Frasson, Chiara;Denaro, Luca;D'Avella, Domenico;Panchision, David M.;Della Puppa, Alessandro;Scienza, Renato;Basso, Giuseppe
髓母细胞瘤是儿童最常见的脑部恶性肿瘤。目前认为，MDB是由小脑中功能异常的干细胞引起的，这些干细胞无法维持对自我更新的适当控制。此外，据报道，MDB细胞表现出更高的内源性Notch信号激活，已知可促进肿瘤神经干细胞的存活和增殖，并抑制其分化。虽然缺氧诱导因子-1α (HIF-1α)和Notch信号之间的相互作用是维持正常神经前体处于未分化状态所必需的，但在MDB中尚未发现相互作用。在这里，我们研究缺氧是否通过HIF-1α稳定化，调节原代mdb来源细胞中的Notch1信号。我们的研究结果表明，mdb衍生的前体细胞需要缺氧条件才能在体外扩增，而急性暴露于20%的氧气下通过抑制Notch信号传导诱导肿瘤细胞分化和死亡。重要的是，在缺氧条件下，通过其配体Dll4刺激Notch1激活可导致mdb衍生的CD133+和巢蛋白+前体的扩增，这表明Notch1对干细胞具有调节作用。相反，当用γ-分泌酶抑制剂处理时，MDB细胞会发生神经元分化，从而阻止Notch激活。这些结果表明，缺氧通过维持Notch1的活性形式，保持MDB干细胞的活力和扩增。
Medulloblastoma (MDB) is the most common brain malignancyof childhood. It is currently thought that MDB arises from aberrantly functioning stem cells in the cerebellum that fail to maintain proper control of self-renewal. Additionally, it has been reported that MDB cells display higher endogenous Notch signaling activation, known to promote the survival and proliferation of neoplastic neural stem cells and to inhibit their differentiation. While interaction between Hypoxia Inducible Factor-1α (HIF-1α) and Notch signalling is required to maintain normal neural precursors in an undifferentiated state, an interaction has not been identified in MDB. Here we investigate whether hypoxia, through HIF-1α stabilization, modulates Notch1 signaling in primary MDB-derived cells. Our results indicate that MDB-derived precursor cells require hypoxic conditions for in vitro expansion, whereas acute exposure to 20% oxygen induces tumor cell differentiation and death through inhibition of Notch signaling. Importantly, stimulating Notch1 activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDB-derived CD133+ and nestin+ precursors, suggesting a regulatory effect on stem cells. In contrast, MDB cells undergo neuronal differentiation when treated with γ-secretase inhibitor, which prevents Notch activation. These results suggest that hypoxia, by maintaining Notch1 in its active form, preserves MDB stem cell viability and expansion.
登录
查看更多内容
DOI：
10.4161/cc.8.20.9701
发表时间：
2009-10-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Heddleston JM;Li Z;McLendon RE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN
影响因子：
3.5
作者：
Indraccolo, S;Roni, V;Amadori, A
通讯作者：
Amadori, A
DOI：
10.1073/pnas.102660199
发表时间：
2002-05-14
影响因子：
11.1
作者：
Jögi, A;Ora, I;Påhlman, S
通讯作者：
Påhlman, S
影响因子：
2.3
作者：
Chadwick, Nicholas;Fennessy, Carl;Buckle, Anne-Marie
通讯作者：
Buckle, Anne-Marie
影响因子：
5.2
作者：
Chadwick, Nicholas;Nostro, Maria Cristina;Buckle, Anne-Marie
通讯作者：
Buckle, Anne-Marie