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The role of hypoxia in inflammatory disease (review).

Biddlestone J, Bandarra D, Rocha S - Int. J. Mol. Med. (2015)

Bottom Line: Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation.Several common disease processes are characterised by aberrant transcriptional programs in response to environmental stress.In this review, we discuss the current understanding of the role of the hypoxia-responsive (hypoxia-inducible factor) and inflammatory (nuclear factor-κB) transcription factor families and their crosstalk in rheumatoid arthritis, inflammatory bowel disease and colorectal cancer, with relevance for future therapies for the management of these conditions.

View Article: PubMed Central - PubMed

Affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.

ABSTRACT
Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation. These stimuli commonly occur together in vivo and there is significant crosstalk between the transcription factors that are classically understood to respond to either hypoxia or inflammation. This crosstalk can be used to modulate the overall response to environmental stress. Several common disease processes are characterised by aberrant transcriptional programs in response to environmental stress. In this review, we discuss the current understanding of the role of the hypoxia-responsive (hypoxia-inducible factor) and inflammatory (nuclear factor-κB) transcription factor families and their crosstalk in rheumatoid arthritis, inflammatory bowel disease and colorectal cancer, with relevance for future therapies for the management of these conditions.

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HIF and NF-κB crosstalk in CRC. In CRC, the intestinal lumen is characterised by hypoxic and inflammatory regions (in blue and red, respectively). HIF-1α is activated in hypoxia, and is involved in the modulation of tumour growth, apoptosis, and EMT. Inflammation leads to the activation of NF-κB, which is involved in the expression of pro-inflammatory cytokines, ROS production, and tumour survival. In CRC, there are some points of crosstalk between NF-κB and HIF, namely in the regulation of p53, APC, and cMyc. HIF, hypoxia-inducible factor; NF-κB, nuclear factor-κB; CRC, colorectal cancer; EMT, epithelial to mesenchymal transition; ROS, reactive oxygen species; APC, adenomatous polyposis coli.
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f5-ijmm-35-04-0859: HIF and NF-κB crosstalk in CRC. In CRC, the intestinal lumen is characterised by hypoxic and inflammatory regions (in blue and red, respectively). HIF-1α is activated in hypoxia, and is involved in the modulation of tumour growth, apoptosis, and EMT. Inflammation leads to the activation of NF-κB, which is involved in the expression of pro-inflammatory cytokines, ROS production, and tumour survival. In CRC, there are some points of crosstalk between NF-κB and HIF, namely in the regulation of p53, APC, and cMyc. HIF, hypoxia-inducible factor; NF-κB, nuclear factor-κB; CRC, colorectal cancer; EMT, epithelial to mesenchymal transition; ROS, reactive oxygen species; APC, adenomatous polyposis coli.

Mentions: The role of the HIFs in cancer progression has long been appreciated due to their ability to promote angiogenesis through one of the principally identified HIF-1α target genes, VEGFA (113). However, it is becoming more evident that hypoxia and the HIF system can affect tumour growth through modulation of proliferation, apoptosis and epithelial to mesenchymal transition (EMT) (Fig. 5). Hypoxia and the subsequent HIF activation are generally understood to be prognostically bad and lead to tumour progression (114). In CRC, HIF-1α stabilisation has been shown to lead to a poor disease outcome. Shay et al (114) demonstrated that the inhibition of HIF signalling using acriflavine halted the progression of an autochthonous model of established colitis-associated colon cancer in immuno-competent mice. In their model, treatment with acriflavine was shown to decrease tumour number, size and advancement, in an effect thought to be mediated through the inhibition of HIF-dependent targets, such as VEGFA. These data provide a direct link between HIF-1α expression and tumour progression. However, HIF isoform activation can be antagonistic in the context of tumour progression. In contrast to the effect of high HIF-1α expression, high HIF-2α expression has recently been reported to prevent CRC progression (115). The antagonistic effects of HIF-1α and HIF-2α are important for the regulation of proliferation and apoptosis in cancer biology (40,82,116). The HIF system can affect proliferation through the regulation of cMyc. HIF-1α can promote cell cycle arrest by the direct opposition of c-Myc activity and the induction of p21 in CRC (116). Conversely, HIF-2α has been shown to promote proliferation in through its augmentation of cMyc function (40).


The role of hypoxia in inflammatory disease (review).

Biddlestone J, Bandarra D, Rocha S - Int. J. Mol. Med. (2015)

HIF and NF-κB crosstalk in CRC. In CRC, the intestinal lumen is characterised by hypoxic and inflammatory regions (in blue and red, respectively). HIF-1α is activated in hypoxia, and is involved in the modulation of tumour growth, apoptosis, and EMT. Inflammation leads to the activation of NF-κB, which is involved in the expression of pro-inflammatory cytokines, ROS production, and tumour survival. In CRC, there are some points of crosstalk between NF-κB and HIF, namely in the regulation of p53, APC, and cMyc. HIF, hypoxia-inducible factor; NF-κB, nuclear factor-κB; CRC, colorectal cancer; EMT, epithelial to mesenchymal transition; ROS, reactive oxygen species; APC, adenomatous polyposis coli.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356629&req=5

f5-ijmm-35-04-0859: HIF and NF-κB crosstalk in CRC. In CRC, the intestinal lumen is characterised by hypoxic and inflammatory regions (in blue and red, respectively). HIF-1α is activated in hypoxia, and is involved in the modulation of tumour growth, apoptosis, and EMT. Inflammation leads to the activation of NF-κB, which is involved in the expression of pro-inflammatory cytokines, ROS production, and tumour survival. In CRC, there are some points of crosstalk between NF-κB and HIF, namely in the regulation of p53, APC, and cMyc. HIF, hypoxia-inducible factor; NF-κB, nuclear factor-κB; CRC, colorectal cancer; EMT, epithelial to mesenchymal transition; ROS, reactive oxygen species; APC, adenomatous polyposis coli.
Mentions: The role of the HIFs in cancer progression has long been appreciated due to their ability to promote angiogenesis through one of the principally identified HIF-1α target genes, VEGFA (113). However, it is becoming more evident that hypoxia and the HIF system can affect tumour growth through modulation of proliferation, apoptosis and epithelial to mesenchymal transition (EMT) (Fig. 5). Hypoxia and the subsequent HIF activation are generally understood to be prognostically bad and lead to tumour progression (114). In CRC, HIF-1α stabilisation has been shown to lead to a poor disease outcome. Shay et al (114) demonstrated that the inhibition of HIF signalling using acriflavine halted the progression of an autochthonous model of established colitis-associated colon cancer in immuno-competent mice. In their model, treatment with acriflavine was shown to decrease tumour number, size and advancement, in an effect thought to be mediated through the inhibition of HIF-dependent targets, such as VEGFA. These data provide a direct link between HIF-1α expression and tumour progression. However, HIF isoform activation can be antagonistic in the context of tumour progression. In contrast to the effect of high HIF-1α expression, high HIF-2α expression has recently been reported to prevent CRC progression (115). The antagonistic effects of HIF-1α and HIF-2α are important for the regulation of proliferation and apoptosis in cancer biology (40,82,116). The HIF system can affect proliferation through the regulation of cMyc. HIF-1α can promote cell cycle arrest by the direct opposition of c-Myc activity and the induction of p21 in CRC (116). Conversely, HIF-2α has been shown to promote proliferation in through its augmentation of cMyc function (40).

Bottom Line: Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation.Several common disease processes are characterised by aberrant transcriptional programs in response to environmental stress.In this review, we discuss the current understanding of the role of the hypoxia-responsive (hypoxia-inducible factor) and inflammatory (nuclear factor-κB) transcription factor families and their crosstalk in rheumatoid arthritis, inflammatory bowel disease and colorectal cancer, with relevance for future therapies for the management of these conditions.

View Article: PubMed Central - PubMed

Affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.

ABSTRACT
Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation. These stimuli commonly occur together in vivo and there is significant crosstalk between the transcription factors that are classically understood to respond to either hypoxia or inflammation. This crosstalk can be used to modulate the overall response to environmental stress. Several common disease processes are characterised by aberrant transcriptional programs in response to environmental stress. In this review, we discuss the current understanding of the role of the hypoxia-responsive (hypoxia-inducible factor) and inflammatory (nuclear factor-κB) transcription factor families and their crosstalk in rheumatoid arthritis, inflammatory bowel disease and colorectal cancer, with relevance for future therapies for the management of these conditions.

Show MeSH
Related in: MedlinePlus