title: HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway.
abstract: Hypoxia induces the expansion of glioblastoma stem cells (GSCs), but the mechanism underlying it is still unclear. Here, we supply evidence that hypoxia-inducible factor-1α (HIF-1α) induced activation of Notch pathway is essential for hypoxia-mediated maintenance of GSC. Either depletion of HIF-1α or inactivation of Notch signaling partly inhibits the hypoxia-mediated maintenance of GSC. Further data suggest a role for HIF-1α in the interaction and stabilization of intracellular domain of Notch (NICD), and activation of Notch signaling. The mRNA level of HIF-1α and Notch target gene FABP7 was elevated in GSC. And the STAT3 pathway responsible for the HIF-1α gene transcription, the phosphatidylinositol 3-kinase-Akt and ERK1/2, both of which are contributed to HIF-1α protein translation, are also preferentially activated in GSC. Inhibition of these pathways partly reduces the hypoxia-induced activation of the Notch pathway and subsequent GSC maintenance. Taken together, our findings suggest that HIF-1α requires Notch pathway to drive the maintenance of GSC. The activated regulation of HIF-1α makes GSC more sensitive to hypoxia-mediated maintenance. These findings enhance our understanding of mechanism of hypoxia-mediated GSC expansion and provide HIF-1α as an attractive target for glioblastoma therapy.
authors.affiliation: Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Qiang
authors.forename: T
authors.initials: T
authors.lastname: Wu
authors.forename: H-W
authors.initials: HW
authors.lastname: Zhang
authors.forename: N
authors.initials: N
authors.lastname: Lu
authors.forename: R
authors.initials: R
authors.lastname: Hu
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.forename: F-H
authors.initials: FH
authors.lastname: Chen
authors.forename: X-T
authors.initials: XT
authors.lastname: Wang
authors.forename: Q-D
authors.initials: QD
authors.lastname: You
authors.forename: Q-L
authors.initials: QL
authors.lastname: Guo
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D051880:Receptors, Notch / Q000737:chemistry / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D000099162:Endothelial PAS Domain-Containing Protein 1