ArticleCell death & disease2021
HIF1α/HIF2α-Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR-PI3K/AKT signalling pathway with positive feedback under hypoxia.
Article in Cell death & disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 59 citations in OpenAlex.
- Nrf2 and PGC-1α signaling in temozolomide resistance in glioblastoma under hypoxia.Biomedical reports · 2026Article
- Methyl 4-O-Demethylbarbatate Destabilises HIF-1α and Enhances Temozolomide Sensitivity in Glioma Cells.Cell proliferation · 2026Article
- A Mechanistic Model of the HIF-1/HIF-2 Switch Regulating Hypoxia-Induced Cancer Stemness.International journal of molecular sciences · 2026Article
- Hypoxia-induced endoplasmic reticulum stress mediates lenvatinib resistance in hepatocellular carcinoma through the IRE1α-XBP1s-HIF1α pathway.Journal of cancer research and clinical oncology · 2026Article
- Cellular and inflammatory characteristics of patient‑derived glioblastoma organoids duringOncology reports · 2026Article
- Open micro-valley chip reveals long-term viscosity-induced glioblastoma cellular invasion states.Microsystems & nanoengineering · 2026Article
- Arabica coffee oil extract enhances neuronal resilience under hypoxic stress through HIF-1α and EGFR signaling modulation.BMC complementary medicine and therapies · 2026Article
- Rhythms of risk: the intersection of clocks, cancer, and chronotherapy.The Journal of clinical investigation · 2026Review
- The mechanism of the PI3K-AKT-mTOR signaling pathway in renal cell carcinoma: current developments and future prospects.Frontiers in oncology · 2026Review
- miR-652-5p promoter hypermethylation enhances glioblastoma malignancy through the SDC1/TGFβ2/pERBB4 complex via HIF2α-mediated regulation under hypoxia.Cancer cell international · 2025Article
- Von Hippel-Lindau/Hypoxia Inducible Factor Axis in Glioblastoma.International journal of molecular sciences · 2025Review
- HIF-1α and HIF-2α: synergistic regulation of glioblastoma malignant progression during hypoxia and apparent chemosensitization in response to hyperbaric oxygen.Cancer cell international · 2025Article
- The Metabolic Orchestration of Immune Evasion in Glioblastoma: From Molecular Perspectives to Therapeutic Vulnerabilities.Cancers · 2025Review
- Modulating Cancer Stem Cell Characteristics in CD133+ Melanoma Cells through Hif1α, KLF4, and SHH Silencing.ACS omega · 2025Article
- Temozolomide promotes glioblastoma stemness expression through senescence-associated reprogramming via HIF1α/HIF2α regulation.Cell death & disease · 2025Article
- It's all downstream from here: RTK/Raf/MEK/ERK pathway resistance mechanisms in glioblastoma.Journal of neuro-oncology · 2025Review
- Amino acid metabolism in glioblastoma pathogenesis, immune evasion, and treatment resistance.Cancer cell international · 2025Review
- The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies.International journal of molecular sciences · 2025Review
- Correlation between EGF and VEGF expression levels and the efficacy of radiosurgery in recurrent glioma.American journal of translational research · 2025Article
- Hyperbaric oxygen promotes both the proliferation and chemosensitization of glioblastoma cells by inhibiting HIF1α/HIF2α-ABCG2.Frontiers in molecular neuroscience · 2025Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Previous studies have suggested that hypoxic responses are regulated by hypoxia-inducible factors (HIFs), which in turn promote the malignant progression of glioblastoma (GBM) by inhibiting apoptosis and increasing proliferation; these events lead to a poor prognosis of GBM patients. However, there are still no HIF-targeted therapies for the treatment of GBM. We have conducted series of experiments and discovered that GBM cells exhibit features indicative of malignant progression and are present in a hypoxic environment. Knocking out HIF1α or HIF2α alone resulted in no significant change in cell proliferation and cell cycle progression in response to acute hypoxia, but cells showed inhibition of stemness expression and chemosensitization to temozolomide (TMZ) treatment. However, simultaneously knocking out HIF1α and HIF2α inhibited cell cycle arrest and promoted proliferation with decreased stemness, making GBM cells more sensitive to chemotherapy, which could improve patient prognosis. Thus, HIF1α and HIF2α regulate each other with negative feedback. In addition, HIF1α and HIF2α are upstream regulators of epidermal growth factor (EGF), which controls the malignant development of GBM through the EGFR-PI3K/AKT-mTOR-HIF1α signalling pathway. In brief, the HIF1α/HIF2α-EGF/EGFR-PI3K/AKT-mTOR-HIF1α signalling axis contributes to the growth of GBM through a positive feedback mechanism. Finally, HIF1α and HIF2α regulate Sox2 and Klf4, contributing to stemness expression and inducing cell cycle arrest, thus increasing malignancy in GBM. In summary, HIF1α and HIF2α regulate glioblastoma malignant progression through the EGFR-PI3K/AKT pathway via a positive feedback mechanism under the effects of Sox2 and Klf4, which provides a new tumour development model and strategy for glioblastoma treatment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.