Expression of proinflammatory cytokines via HIF-1α and NF-κB activation on desferrioxamine-stimulated HMC-1 cells

Jeong, Hyun‐Ja; Chung, Hwan‐Suck; Lee, Bora; Kim, Sujin; Yoo, Seung‐Min; Hong, Seung‐Heon; Kim, Hyung-Min

doi:10.1016/s0006-291x(03)01073-8

Cited by 103 publications

(74 citation statements)

References 52 publications

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“…NF-κB can be activated by hypoxia (18,19) and our results have demonstrated that hypoxia increased Hpa expression. However, whether the NF-κB signaling pathway plays an important role in the regulation of Hpa remains unclear.…”

Section: Inhibition Of Nf-κb Decreases the Hpa Protein Levelsupporting

confidence: 58%

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Hypoxia activates heparanase expression in an NF-κB dependent manner

Wang

Pan²,

Meng³

et al. 2009

Oncol Rep

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Abstract. Hypoxia was shown to increase tumor cell invasion into the extracellular matrix in vitro. This result suggests that heparanase (Hpa), one of the key enzymes involved in tumor invasion and metastasis, may be regulated by hypoxia. RT-PCR, Western blot and Matrigel invasive assays were used to study the regulation of Hpa under hypoxia in human pancreatic MIA PaCa-2 cancer cells. Compared with those in normoxia (20% O 2 ), Hpa mRNA, protein and enzymatic activity levels, were up-regulated by a reduction in the oxygen level (1% O 2 ). Invasion by tumor cells into the extracellular matrix was found to be significantly enhanced. A reduction in Hpa protein levels was observed when nuclear factor κB (NF-κB) activation was blocked by pyrrolidine dithiocarbamate. The levels of Hpa were also reduced when Hpa was inhibited by an Hpa-specific antisense oligonucleotide. The MMP-9 mRNA, protein and gelatinase B activity levels in supernatants decreased significantly when Hpa was inhibited. We conclude that up-regulation of Hpa by hypoxia is NF-κB-dependent in MIA PaCa-2 cells and inhibition of Hpa reduces MMP-9 activity. This reduction in MMP-9 activity may be an important mechanism in tumor metastasis. IntroductionHeparanase (Hpa) is an endo-ß-glucuronidase that cleaves the heparin sulfate (HS) side-chain. This enzymatic reaction not only enhances tumor cell invasion and migration, but also releases important HS-binding cytokines relevant to angiogenesis, wound healing and tumor growth. Up-regulation of Hpa has been demonstrated in a number of primary human cancers and correlates with reduced postoperative survival in bladder (1), stomach (2), pancreas (3), colorectal (4) and gallbladder cancers (5). In addition, high levels of Hpa are expressed in patients with lymph nodes and distant metastasis (4-7).In solid tumors, cells are constantly exposed to chronic or acute hypoxia (8). In vitro studies have reported that tumor cells exposed to hypoxia exhibit an increased ability to invade the extracellular matrix (ECM) (9,10). Consequently, understanding the regulation and mutual relationship of degrading enzymes in hypoxic conditions is particularly important. It has been shown that high level of heparanase molecules may serve some species to adapt to severe hypoxic environment in spalax blind subterrance mole rat (11). In addition, a recent study showed that heparanase gene expression was increased in the brain tissue of rats subjected to repeated hypoxic exposures (12). Hpa activity was shown to be up-regulated by hypoxia in ovarian OC-MZ-6 cancer cell (13). However, information describing the mechanism of the regulation of Hpa and the relationship between degrading enzymes and hypoxia remains unresolved.In this study, we have characterized the regulation of Hpa in hypoxia using the human pancreatic cancer cell line MIA PaCa-2. The results showed that Hpa mRNA, protein and enzymatic activity levels were up-regulated by hypoxia, which is closely related to enhanced tumor cell invasion. Furthermore, up-regulation of Hpa ...

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Section: Inhibition Of Nf-κb Decreases the Hpa Protein Levelsupporting

confidence: 58%

“…NF-κB is an important transcriptional factor which regulates a number of genes involved in immunoreactions, apoptosis, tumor genesis and therapeutic resistance. In hypoxia, NF-κB can easily be activated in vitro in normal and transformed cells (18,19). Research on the relationship between NF-κB and Hpa activity is limited and conflicting.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia activates heparanase expression in an NF-κB dependent manner

Wang

Pan²,

Meng³

et al. 2009

Oncol Rep

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“…7) In mammalian cells, MAPKs signaling cascade plays an essential role in the initiation of inflammatory responses. 8) Three major MAPKs have been defined: the ERK pathway, the stress-activated pathways of the JNK, and the p38 MAPKs.…”

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confidence: 99%

Inactivation of Cystein-Aspartic Acid Protease (Caspase)-1 by Saikosaponin A

Han

Kim

Jeong

2011

Biological & Pharmaceutical Bulletin

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This work investigates the anti-inflammatory mechanism of saikosaponin A (SA), a major component of Bupleurum falcatum LINNE. SA significantly inhibited phorbol myristate acetate (PMA) plus A23187-induced the production and expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-a a in human mast cell (HMC)-1 cells. SA suppressed PMA plus A23187-induced phosphorylation of extracellular signal-regulated kinase and p38. When HMC-1 cells were treated with SA, translocation of nuclear factor (NF)-k kB/Rel A into nucleus and degradation of inhibitor of NF-k kB (Ik kB) in cytoplasm were inhibited. SA decreased PMA plus A23187-induced cystein-aspartic acid protease (caspase)-1 activity. IL-1b b production was also inhibited by SA. Finally, SA significantly decreased the number of nasal rubs and serum TNF-a a level in the ovalbumin-sensitized allergic rhinitis mouse model. The underlying mechanism involves, at least in part, inactivation of caspase-1, which provides new evidence for therapeutic application of SA to target inflammatory processes.

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“…In leucocytes, which function as a key factor in the development and progression of atherosclerotic lesions, HIF-1α has been reported to have a direct effect on the cytokine profile (24). Jeong et al also reported that activation of HIF-1α in mast cells could stimulate the expression of VEGF, leading to direct and indirect attraction of inflammatory cells into the intima in various stages of atherogenesis (25,26). Moreover, a number of studies have established the crucial role of HIF-1α in vascular smooth muscle cells proliferation exposed to hypoxic stimulus (27).…”

Section: Discussionmentioning

confidence: 99%