Carmeliet, P. et al. Role of HIF-1 in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485-490

Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Belgium.
Nature (Impact Factor: 41.46). 08/1998; 394(6692):485-90. DOI: 10.1038/28867
Source: PubMed


As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced. Hypoxia-inducible factor (HIF)-1alpha helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis. Here we show that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (HIF-1alpha+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1alpha genes (HIF-1alpha-/-); however, a deficiency of HIF-1alpha does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1alpha-dependent (those encoding the proteins p53, p21, Bcl-2) or HIF-1alpha-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients. Loss of HIF-1alpha reduces hypoxia-induced expression of vascular endothelial growth factor, prevents formation of large vessels in ES-derived tumours, and impairs vascular function, resulting in hypoxic microenvironments within the tumour mass. However, growth of HIF-1alpha tumours was not retarded but was accelerated, owing to decreased hypoxia-induced apoptosis and increased stress-induced proliferation. As hypoxic stress contributes to many (patho)biological disorders, this new role for HIF-1alpha in hypoxic control of cell growth and death may be of general pathophysiological importance.

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    • "Within the cell, molecular oxygen is tightly regulated, and a key component of this oxygen-sensing pathway is the transcription factor HIF (Wang and Semenza, 1993, 1995). HIF is important for the adaptation of the cell during periods of reduced oxygen availability and its activation promotes the expression of numerous genes, including those involved in erythropoiesis (Semenza and Wang, 1992), vascular development and angiogenesis (Carmeliet et al., 1998; Iyer et al., 1998), and glycolysis (Semenza et al., 1994). HIF is a heterodimer consisting of two subunits, a constitutively present HIF1b (Aryl Hydrocarbon Nuclear Receptor Translocator, ARNT) (Wang et al., 1995), and HIF1a, a subunit that is expressed in hypoxic conditions (Wang and Semenza, 1993). "
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    ABSTRACT: Exercise reduces the risk of developing a number of neurological disorders and increases the efficiency of cellular energy production. However, overly strenuous exercise produces oxidative stress. Proper oxygenation is crucial for the health of all tissues, and tight regulation of cellular oxygen is critical to balance O2 levels and redox homeostasis in the brain. Hypoxia Inducible Factor (HIF)1α and HIF2α are transcription factors regulated by cellular oxygen concentration that initiate gene regulation of vascular development, redox homeostasis, and cell cycle control. HIF1α and HIF2α contribute to important adaptive mechanisms that occur when oxygen and ROS homeostasis become unbalanced. It has been shown that preconditioning by exposure to a stressor prior to a hypoxic event reduces damage that would otherwise occur. Previously we reported that three months of exercise protects SNpc DA neurons from toxicity caused by Complex I inhibition. Here, we identify the cells in the SNpc that express HIF1α and HIF2α and show that running exercise produces hypoxia in SNpc DA neurons, and alters the expression of HIF1α and HIF2α. In mice carrying a conditional knockout of Hif1α in postnatal neurons we observe that exercise alone produces SNpc TH+ DA neuron loss. Loss of HIF1α also abolishes exercise-induced neuroprotection. In mice lacking Hif2α in postnatal neurons, the number of TH+ DA neurons in the adult SNpc is diminished, but three months of exercise rescues this loss. We conclude that HIF1α is necessary for exercise-induced neuroprotection and both HIF1α and HIF2α are necessary for the survival and function of adult SNpc DA neurons. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Full-text · Article · Mar 2015 · Neuroscience
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    • "Under hypoxic conditions, low oxygen levels preclude proline hydroxylation, which leads to HIF-1α stabilization and subsequent formation of a heterodimer with constitutively expressed HIF-1β. The bioactive HIF-1 dimer regulates, as a transcription factor, the expression of a broad range of genes involved not only in cell cycle, apoptosis [9], angiogenesis [10], [11] and metabolism [12] in response to the hypoxic environment, but also in a cellular process called epithelial-mesenchymal transition (EMT) [13]–[15]. "
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    ABSTRACT: The prognosis of patients with ovarian cancer has remained poor mainly because of aggressive cancer progression. Since epithelial-mesenchymal transition (EMT) is an important mechanism mediating invasion and metastasis of cancer cells, targeting the EMT process with more efficacious and less toxic compounds to inhibit metastasis is of great therapeutic value for the treatment of ovarian cancer. We have found for the first time that the ginsenoside 20(S)-Rg3, a pharmacologically active component of the traditional Chinese herb Panax ginseng, potently blocks hypoxia-induced EMT of ovarian cancer cells in vitro and in vivo. Mechanistic studies confirm the mode of action of 20(S)-Rg3, which reduces the expression of hypoxia-inducible factor 1α (HIF-1α) by activating the ubiquitin-proteasome pathway to promote HIF-1α degradation. A decrease in HIF-1α in turn leads to up-regulation, via transcriptional suppression of Snail, of the epithelial cell-specific marker E-cadherin and down-regulation of the mesenchymal cell-specific marker vimentin under hypoxic conditions. Importantly, 20(S)-Rg3 effectively inhibits EMT in nude mouse xenograft models of ovarian cancer, promising a novel therapeutic agent for anticancer therapy.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Moreover, other authors have shown that, compared with wild type tumors, tumors that lack HIF-1α are poorly vascularized but are faster growing, perhaps because of a loss of dependency upon neovascularization. These findings would be consistent with the increased response rate and improved prognosis observed in our series for patients over-expressing miR-107 [30, 31]. In addition, overexpression of miR-107 has been recently shown in gastric cancers in comparison with normal tissue, and up-regulation of these miRNA increased the proliferation of gastric cancer cells [32]. "
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    ABSTRACT: MicroRNAs (miRNAs) are involved in numerous biological and pathological processes including colorectal cancer (CRC). The aim of our study was to evaluate the ability of miRNA expression patterns to predict chemotherapy response in a cohort of 78 patients with metastatic CRC (mCRC). We examined expression levels of 667 miRNAs in the training cohort and evaluated their potential association with relevant clinical endpoints. We identified a miRNA profile that was analysed by RT-qPCR in an independent cohort. For a set of selected miRNAs, bioinformatic target predictions and pathway analysis were also performed. Eight miRNAs (let-7 g*, miR-107, miR-299-5p, miR-337-5p, miR-370, miR-505*, miR-889 and miR-99a-3p) were significant predictors of response to chemotherapy in the training cohort. In addition, overexpression of miR-107, miR-337-5p and miR-99a-3p, and underexpression of miR-889, were also significantly associated with improved progression-free and/or overall survival. MicroRNA-107 and miR-99a-3p were further validated in an independent cohort as predictive markers for chemotherapy response. In addition, an inverse correlation was confirmed in our study population between miR-107 levels and mRNA expression of several potential target genes (CCND1, DICER1, DROSHA and NFKB1). MiR-107 and miR-99a-3p were validated as predictors of response to standard fluoropyrimidine-based chemotherapy in patients with mCRC.
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