Inflammatory interferon activates HIF-1α-mediated epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Tumor microenvironments (TMEs) involve complex interactions, including inflammation and hypoxia, which drive cancer progression and treatment resistance.
• The interplay between hypoxia and inflammation in TMEs is not fully understood, necessitating research into their combined effects.

Purpose of the Study:

• To investigate whether interferon (IFN) can modulate both inflammatory and hypoxic responses.
• To explore the role of IFN in cancer development by examining its impact on hypoxia-inducible factor 1-alpha (HIF-1α) and related pathways.

Main Methods:

• IFN was used to induce inflammation and HIF-1α expression in cancer cell lines.
• Signaling pathways were analyzed using inhibitors, immunoblotting, and knockdown approaches.
• IFN-induced epithelial-mesenchymal transition (EMT) and tumorigenic properties were assessed via various in vitro and in vivo assays.

Main Results:

• IFN induced functional HIF-1α expression in cancer cells under normoxic and hypoxic conditions, activating the HIF-1α pathway in an inflammatory TME.
• IFN regulated anti-apoptosis, metastasis, EMT, and vasculogenic mimicry via PI3K/AKT/mTOR axis activation.
• HIF-1α was essential for IFN-induced invasiveness, tumorigenesis, and vasculogenic mimicry, confirmed in xenograft models.

Conclusions:

• IFN induces HIF-1α and EMT in inflammatory TMEs, revealing a novel link between inflammatory and hypoxic TMEs.
• Targeting HIF-1α presents a potential strategy to inhibit tumor progression and EMT.
• The findings provide a rationale for developing therapies targeting IFN signaling and HIF-1α programming to prevent cancer relapse.