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IL‐1β mediated up‐regulation of HIF‐lα via an NFkB/COX‐2 pathway identifies HIF‐1 as a critical link between inflammation and oncogenesis
Author(s) -
Jung Yun-Jin,
Isaacs Jennifer S.,
Lee Sunmin,
Trepel Jane,
Neckers Len
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0329fje
Subject(s) - transcription factor , inflammation , cancer research , signal transduction , pi3k/akt/mtor pathway , carcinogenesis , effector , protein kinase b , cytokine , microbiology and biotechnology , vascular endothelial growth factor , hif1a , angiogenesis , biology , chemistry , immunology , cancer , biochemistry , vegf receptors , genetics , gene
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 E 2 (PGE 2 ), 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.