HIF1α/HIF2α-Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR-PI3K/AKT signalling pathway with positive feedback under hypoxia

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 HIF1 alpha or HIF2 alpha 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 HIF1 alpha and HIF2 alpha inhibited cell cycle arrest and promoted proliferation with decreased stemness, making GBM cells more sensitive to chemotherapy, which could improve patient prognosis. Thus, HIF1 alpha and HIF2 alpha regulate each other with negative feedback. In addition, HIF1 alpha and HIF2 alpha are upstream regulators of epidermal growth factor (EGF), which controls the malignant development of GBM through the EGFR-PI3K/AKT-mTOR-HIF1 alpha signalling pathway. In brief, the HIF1 alpha /HIF2 alpha -EGF/EGFR-PI3K/AKT-mTOR-HIF1 alpha signalling axis contributes to the growth of GBM through a positive feedback mechanism. Finally, HIF1 alpha and HIF2 alpha regulate Sox2 and Klf4, contributing to stemness expression and inducing cell cycle arrest, thus increasing malignancy in GBM. In summary, HIF1 alpha and HIF2 alpha 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.

Automated summary

HIF1α and HIF2α regulate each other with a negative feedback loop, affecting GBM malignant progression through the EGFR-PI3K/AKT pathway and increasing sensitivity to chemotherapy. Their interaction with Sox2 and Klf4 further contributes to stemness expression and cell cycle arrest, enhancing malignancy in GBM.