Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 that is encoded by the HIF1A gene. The Nobel Prize in Physiology or Medicine 2019 was awarded for the discovery of HIF.

Hypoxia has long been recognized as a driving force of tumor progression and therapeutic resistance, and the transcription factor HIF-1α is believed to play a crucial role in these processes.

Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1A.

Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a protein that in humans is encoded by the HIF1A gene.

Two alternative transcripts encoding different isoforms have been identified.

The protein encoded by HIF1 is a bHLH - PAS transcription factor found in mammalian cells growing at low oxygen concentrations. It plays an essential role in cellular and systemic responses to hypoxia.

This is one of the classes of hypoxia-inducible factors, a family that includes Hif1a, Hif2a, and Hif3a.

HIF1A and HIF2A are the two main molecules that contribute to Glioblastoma malignant progression by inhibiting apoptosis or maintaining stemness under hypoxic conditions. Moreover, Sox2, a marker of stemness, also contribute to Glioblastoma malignant progression through stemness maintenance of cell cycle arrest. Briefly, HIF1α, HIF2α, and Sox2 are highly expressed under hypoxia and contribute to Glioblastoma growth and chemoresistance. However, after exposure to HBO for Glioblastoma, whether the expression of the above factors is decreased, resulting in chemosensitization, remains unknown. Therefore, Wang et al. performed a series of studies and determined that the expression of HIF1α, HIF2α, and Sox2 was decreased after HBO and that HBO promoted Glioblastoma cell proliferation through cell cycle progression, albeit with a decrease in stemness, thus contributing to chemosensitization via the inhibition of HIF1α/HIF2α-Sox2 ¹⁾.

Using an orthotopic mouse model with U87-LucNeo cells, the authors used RNA interference to knock down HIF-1α in vivo. The small interfering RNA (siRNA) was packaged using a novel multifunctional surfactant, 1-(aminoethyl) iminobis[N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide] (EHCO), a nucleic acid carrier that facilitates cellular uptake and intracellular release of siRNA. Stereotactic injection was used to deliver siRNA locally through a guide-screw system, and delivery/uptake was verified by imaging of fluorescently labeled siRNA. Osmotic pumps were used for extended siRNA delivery to model a commonly used human intracranial drug-delivery technique, convection-enhanced delivery.

Mice receiving daily siRNA injections targeting HIF-1α had a 79% lower tumor volume after 50 days of treatment than the controls. Levels of the HIF-1 transcriptional targets vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), c-MET, and carbonic anhydrase-IX (CA-IX) and markers for cell growth (MIB-1 and microvascular density) were also significantly lower. Altering the carrier EHCO by adding polyethylene glycol significantly increased the efficacy of drug delivery and subsequent survival.

Treating glioblastoma with siRNA targeting HIF-1α in vivo can significantly reduce tumor growth and increase survival in an intracranial mouse model, a finding that has direct clinical implications ²⁾.

Miroshnikova et al., found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR 203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. The work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status ³⁾.

Hypoxia-inducible factor-1α (HIF1a) contributes substantially to the stemness maintenance of glioma stem cells (GSCs) and resistance of glioma to chemotherapy; thus, they investigated whether HIF1α regulates the resistance or sensitization of glioma cells to chemotherapy in different oxygen levels. It highlights a novel viewpoint on glioma chemosensitivity from the transformation between dedifferentiation and differentiation in different oxygen levels ⁴⁾.