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PMID:12958148

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Citation

Jung, YJ, Isaacs, JS, Lee, S, Trepel, J and Neckers, L (2003) IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J. 17:2115-7

Abstract

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-1alpha is a factor linking inflammation and tumorigenesis, we investigated whether the HIF-1 signaling pathway was stimulated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in A549 cells. We find that IL-1beta up-regulated HIF-1alpha protein under normoxia and activated the HIF-1-responsive gene vascular endothelial growth factor (VEGF) via a pathway dependent on nuclear factor kappaB (NFkB). Interestingly, although this pathway is stimulated by upstream signaling via AKT and mTOR and requires new transcription, IL-1 mediated HIF-1alpha induction also utilizes a post-transcriptional mechanism that involves antagonism of VHL-dependent HIF-1alpha degradation, which results in increased HIF-1alpha protein stability. IL-1 mediated NFkB-dependent cyclooxygenases-2 (COX-2) expression served as a positive effector for HIF-1alpha induction. Although COX-2 inhibitors attenuated IL-1 mediated HIF-1alpha induction, prostaglandin E2 (PGE2), a physiological product of COX-2, induced HIF-1alpha protein in a dose-dependent manner. Our data, therefore, demonstrate that IL-1beta up-regulates functional HIF-1alpha 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.

Links

PubMed Online version:10.1096/fj.03-0329fje

Keywords

Cell Line, Tumor; Cyclooxygenase 2; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation/complications; Interleukin-1/pharmacology; Isoenzymes/metabolism; Membrane Proteins; NF-kappa B/metabolism; Neoplasms/etiology; Neoplasms/metabolism; Phosphatidylinositol 3-Kinases/metabolism; Prostaglandin-Endoperoxide Synthases/metabolism; Signal Transduction; Transcription Factors/biosynthesis; Tumor Suppressor Proteins/physiology; Ubiquitin-Protein Ligases/physiology; Up-Regulation; Vascular Endothelial Growth Factor A/biosynthesis; Von Hippel-Lindau Tumor Suppressor Protein

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HIF1A

involved_in

GO:0071347: cellular response to interleukin-1

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HIF1A

involved_in

GO:0030949: positive regulation of vascular endothelial growth factor receptor signaling pathway

ECO:0000305: curator inference used in manual assertion

GO:0010573

P

Seeded From UniProt

complete

HUMAN:HIF1A

involved_in

GO:0010573: vascular endothelial growth factor production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NFKB1

involved_in

GO:0071347: cellular response to interleukin-1

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IL1B

involved_in

GO:0051092: positive regulation of NF-kappaB transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IL1B

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IL1B

involved_in

GO:0030949: positive regulation of vascular endothelial growth factor receptor signaling pathway

ECO:0000305: curator inference used in manual assertion

GO:0010575

P

Seeded From UniProt

complete


See also

References

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