HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway
Open accessAbstract
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.
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Stem-like tumor cells (CD133+ or CD44+) in the perivascular niche are thought to cause recurrence and treatment resistance in GBM.
“Stem-like tumor cells (CD133+ or CD44+) in the perivascular niche are thought to be a cause of disease recurrence and treatment resistance in GBM [49].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [49]
The Results (page unavailable) identify CD133-positive cells as enriching glioblastoma stem cells, and the Discussion (page unavailable) reports that glioblastoma-derived tumor spheres show relative resistance to doxorubicin. The copy does not place these cells in a perivascular niche, identify CD44-positive cells, or say they cause GBM recurrence. (LLM, conf=0.86)
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Self-citation
- Authors
- Qiang, L., Wu, T., Zhang, H.-W., Lu, N., Hu, R., Wang, Y.-J., Zhao, L., Chen, F.-H., Wang, X.-T., You, Q.-D., & Guo, Q.-L.
- Affiliations
- China Pharmaceutical University (CN)
- Florida International University (US)
- Corresponding author
- You, Q-D
- Guo, Q-L
- Venue
- Cell Death & Differentiation
- Published
- 2011-08-05
- Volume
- 19
- Issue
- 2
- Pages
- 284-294
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3263503
- OpenAlex
- W2083098015
- Semantic Scholar
- b666010de312d5ad677222181ca254dff20d8b94
- Cited by
- 313
- References
- 43
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 16 · 2023: 24 · 2022: 36 · 2021: 31 · 2020: 17 · 2019: 15 · 2018: 26 · 2017: 30 · 2016: 21 · 2015: 27 · 2014: 11 · 2013: 15 · 2012: 14
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (30701032, 91029744, 90713038, 30472044)
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province (91029744, BK2009297)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- HIF-1α, glioblastoma stem cells, hypoxia, Notch signaling, FABP7, STAT3 pathway, PI3K/Akt signaling, MAPK/ERK pathway, glioblastoma therapy
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Glioblastoma, Humans, Models, Biological, Protein Binding, Transcription, Genetic, Tumor Cells, Cultured, Neoplastic Stem Cells, Signal Transduction, Cell Hypoxia, Protein Structure, Tertiary, Spheroids, Cellular, STAT3 Transcription Factor, Rats, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Receptors, Notch
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