IL-1β mediated up-regulation of HIF-1α via an NFkB/COX- 2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis

Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. To examine whether HIF-1α is a factor linking inflammation and tumorigenesis, we investigated whether the HIF-1 signaling pathway was stimulated by the pro-inflammatory cytokine interleukin-1β (IL-1β) in A549 cells. We find that IL-1β up-regulated HIF-1α protein under normoxia and activated the HIF-1-responsive gene vascular endothelial growth factor (VEGF) via a pathway dependent on nuclear factor κB (NFkB). Interestingly, although this pathway is stimulated by upstream signaling via AKT and mTOR and requires new transcription, IL-1 mediated HIF-1α induction also utilizes a post-transcriptional mechanism that involves antagonism of VHL-dependent HIF-1α degradation, which results in increased HIF-1α protein stability. IL-1 mediated NFkB-dependent cyclooxygenases-2 (COX-2) expression served as a positive effector for HIF-1α induction. Although COX-2 inhibitors attenuated IL-1 mediated HIF-1α induction, prostaglandin E2 (PGE2), a physiological product of COX-2, induced HIF-1α protein in a dose-dependent manner. Our data, therefore, demonstrate that IL-1β up-regulates functional HIF-1α protein through a classical inflammatory signaling pathway involving NFkB and COX-2, culminating in up-regulation of VEGF, a potent angiogenic factor required for tumor growth and metastasis. Thus, HIF-1 is identified as a pivotal transcription factor linking the inflammatory and oncogenic pathways.