HIF Transcription Factors, Inflammation, and Immunity

Palazón, Asís; Goldrath, Ananda W.; Nizet, Victor; Johnson, Randall S.

doi:10.1016/j.immuni.2014.09.008

Cited by 986 publications

(898 citation statements)

References 116 publications

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“…The expression of the transcription factor HIF‐1α is elevated in response to low‐oxygen conditions. HIF‐1α is involved in multiple cellular functions, including blood vessel formation, cell proliferation, immunity and inflammatory responses 6, 7. As shown in our previous studies, HIF‐1α expression is significantly increased in PQ‐treated rat lung tissues, and EMT is also observed.…”

Section: Introductionmentioning

confidence: 63%

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

Zhu

Meng

Xie

et al. 2017

J Cellular Molecular Medi

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Irreversible pulmonary fibrosis induced by paraquat (PQ) poisoning is the major cause of death in patients with PQ poisoning. The epithelial–mesenchymal transition (EMT) is postulated to be one of the main mechanisms of pulmonary fibrosis. Here, we investigated the role of miR‐210 in PQ‐induced EMT and its relationship with hypoxia‐inducible factor‐1α (HIF‐1α). Western blotting, immunofluorescence, immunoprecipitation and other methods were used in this study. We found that miR‐210 expression was significantly increased after PQ poisoning, and it may be regulated by HIF‐1α. Overexpression of miR‐210 further increased the HIF‐1α protein level and promoted EMT. Moreover, miR‐210 knock‐down reduced the HIF‐1α protein level and decreased the degree of EMT. Runt‐related transcription factor‐3 (RUNX3), a direct target of miR‐210, was inhibited by miR‐210 in response to PQ poisoning. RUNX3 increased the hydroxylation ability of prolyl hydroxylase domain‐containing protein 2 (PHD2), a key enzyme that promotes HIF‐1α degradation. PHD2 immunoprecipitated with RUNX3 and its level changed similarly to that of RUNX3. The expression of the HIF‐1α protein was significantly reduced when RUNX3 was overexpressed. HIF‐1α protein levels were markedly increased when RUNX3 was silenced. Based on these results, a positive feedback loop may exist between miR‐210 and HIF‐1α. The mechanism may function through miR‐210‐mediated repression of RUNX3, which further decreases the hydroxylation activity of PHD2, enhances the stability of HIF‐1α, and promotes PQ‐induced EMT, aggravating the progression of pulmonary fibrosis. This study further elucidates the mechanism of PQ‐induced pulmonary fibrosis and may provide a new perspective for the future development of therapies.

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Section: Introductionmentioning

confidence: 63%

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

Zhu

Meng

Xie

et al. 2017

J Cellular Molecular Medi

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“…Although the impact of HIFs on immune responses has been observed (39), the mechanisms by which VHL affects the cellular immunity response, either directly or through HIFs, is still largely unknown. Interestingly, it was reported that pVHL could inhibit NF-kB phosphorylation through its effect on the NF-kB agonist Card 9, which links pVHL to control of NF-kB activity and tumorigenesis (40).…”

Section: Discussionmentioning

confidence: 99%

pVHL Negatively Regulates Antiviral Signaling by Targeting MAVS for Proteasomal Degradation

Zhang

et al. 2015

The Journal of Immunology

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The von Hippel–Lindau (VHL) gene is a well-defined tumor suppressor linked to human heredity cancer syndromes. As a component of the VHL-elongin B/C E3 ligase complex, pVHL performs its tumor function by targeting proteins for proteasomal degradation. It is largely unknown whether pVHL functions in antiviral immunity. In this article, we identify that pVHL negatively regulates innate antiviral immunity, which acts mainly by inducing degradation of mitochondrial antiviral-signaling protein (MAVS, also known as Cardif, IPS-1, or VISA). Overexpression of pVHL abrogated the cellular response to viral infection, whereas knockdown of pVHL exerted the opposite effect. pVHL targeted the K420 residue of MAVS to catalyze the formation of K48-linked polyubiquitin chains, leading to proteasomal degradation of MAVS. After viral infection, Mavs levels remained low in wild type zebrafish embryos but became much higher in vhl-deficient (vhl−/−) zebrafish embryos. Higher MAVS levels correlated with a greatly exaggerated antiviral response. In this work, we demonstrate that pVHL exhibits a previously unknown role in innate antiviral immunity.

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“…Another crucial player is HIF-1, a well-studied transcriptional factor inducing VEGF production and conveying resistance for antitumor drugs (40). Beyond its role in angiogenesis, HIF has been shown to regulate, and be regulated by, many metabolic and inflammatory mediators, including mTOR (11,41,42). Everolimus-mediated blockage of mTOR activity may downregulate HIF-1 function, potentially impacting bevacizumab resistance.…”

Section: Discussionmentioning

confidence: 99%

Biomarker Signatures Correlate with Clinical Outcome in Refractory Metastatic Colorectal Cancer Patients Receiving Bevacizumab and Everolimus

Liu

Starr

Brady

et al. 2015

Molecular Cancer Therapeutics

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A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-a, IGFBP-1, TF, ICAM-1, and TSP-2 (P < 0.05). At C2D1, changes of IGFBP-3, TGFb-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (P ¼ 0.0002 and 0.004, respectively). The baseline model for OS consisted of CRP, Gro-a, and TF, while the on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFb-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology.

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HIF Transcription Factors, Inflammation, and Immunity

Cited by 986 publications

References 116 publications

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

pVHL Negatively Regulates Antiviral Signaling by Targeting MAVS for Proteasomal Degradation

Biomarker Signatures Correlate with Clinical Outcome in Refractory Metastatic Colorectal Cancer Patients Receiving Bevacizumab and Everolimus

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