Hypoxia-regulated target genes implicated in tumor metastasis

Tsai, Ya-Ping; Wu, Kou-Juey

doi:10.1186/1423-0127-19-102

Cited by 173 publications

(144 citation statements)

References 78 publications

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“…Other genes/pathways implicated in this hypoxic response include nuclear factor k B, activator protein-1, mammalian target of rapamycin kinase and the unfolded protein response. [59][60][61] Although these genes/pathways are activated independently, indicating redundancy in oxygen-sensitive pathways, there is also evidence that they can respond to hypoxia in an integrated manner. 62 Early studies have shown that hypoxia selected for cells with defects in apoptosis.…”

Section: Variability In Tumour Oxygenationmentioning

confidence: 99%

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

McKeown

2014

BJR

803

712

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Tumour hypoxia is increasingly recognized as a major deleterious factor in cancer therapies, as it compromises treatment and drives malignant progression. This review seeks to clarify the oxygen levels that are pertinent to this issue. It is argued that normoxia (20% oxygen) is an extremely poor comparator for "physoxia", i.e. the much lower levels of oxygen universally found in normal tissues, which averages about 5% oxygen, and ranges from about 3% to 7.4%. Importantly, it should be recognized that the median oxygenation in untreated tumours is significantly much lower, falling between approximately 0.3% and 4.2% oxygen, with most tumours exhibiting median oxygen levels ,2%. This is partially dependent on the tissue of origin, and it is notable that many prostate and pancreatic tumours are profoundly hypoxic. In addition, therapy can induce even further, often unrecognized, changes in tumour oxygenation that may vary longitudinally, increasing or decreasing during treatment in ways that are not always predictable. Studies that fail to take cognizance of the actual physiological levels of oxygen in tissues (approximately 5%) and tumours (approximately 1%) may fail to identify the real circumstances driving tumour response to treatment and/or malignant progression. This can be of particular importance in genetic studies in vitro when comparison to human tumours is required.

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Section: Variability In Tumour Oxygenationmentioning

confidence: 99%

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

McKeown

2014

BJR

803

712

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“…They positively regulate the expression levels of >100 target genes, which encode protein products involved in the response to hypoxia (3)(4)(5). Tumor hypoxia was first described in the 1950s and currently there is increasing evidence to demonstrate that hypoxia is regulated by HIFs and is a common feature in several types of cancer (6)(7)(8)(9). In 1992, Semenza et al (10) identified a nuclear factor, which binds to the 3'-flanking sequence of the human erythropoietin gene (EPO) and promotes the expression of EPO under anoxic conditions.…”

Section: Introductionmentioning

confidence: 99%

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Yang

Xiong

et al. 2015

Molecular Medicine Reports

110

103

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Abstract. Hypoxia inducible factors (HIFs) are transcription factors, which are commonly expressed in mammals, including humans. The HIFs consist of hypoxia-regulated α and oxygen-insensitive β subunits, and are key regulators of gene expression during hypoxia in normal and solid tumor tissues. Three members of the HIF family, HIF-1α, HIF-2α, and HIF-3α, are currently known. HIF-3α differs from HIF-1α and HIF-2α in protein structure and regulation of gene expression. For a long time, HIF-3α was considered as a negative mediator of HIF-regulated genes. HIF-3 has a transcriptional regulatory function, which negatively affects gene expression by competing with HIF-1α and HIF-2α in binding to transcriptional elements in target genes during hypoxia. Previously, certain target genes of HIF-3α have been identified, confirming the role of HIF-3α as a transcription factor. In this review, the protein structure, gene regulation and biological function of HIF-3 are discussed based on the literature.

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“…[7][8][9][10][11]14 To survive in hypoxia, cells activate adaptive responses, including gene regulation by hypoxia-inducible factors (HIF)-1alpha (HIF-1α) and -2alpha (HIF-2α). 15,16 Hypoxia allows HIF to escape from normoxia-mediated degradation in the cytoplasm and to translocate into nuclei where they bind to hypoxia-response elements within the regulatory regions of target genes [17][18][19][20] and microRNA. 21,22 The use of HIF inhibitors represents a new strategy for the development of therapies targeting the hypoxic cancer microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o ndromes for its deletion on chromosome 5 37 and in the progression of chronic myeloid leukemia. 38 We previously identified the molecular mechanism that regulates the level of CXCR4 protein expression by miR146a targeting 29 (miR-146a/CXCR4) during monocytopoiesis. 39 We also reported that in acute monocytic leukemia (AML-M5), a high CXCR4 protein level is associated with low/absent miR-146a expression. 39 We then showed that enforced miR-146a expression in leukemic cells decreases the level of CXCR4 protein and improves the sensitivity of these cells to drugs. 39CXCR4 is a target gene of HIF-1α and a post-transcriptional target of miR-146a, 9,39 in monocytic cells, known to originate from a common myeloid precursor in the bone marrow giving rise to tissue macrophages and dendritic cells 40 and subject to very different oxygen (O 2 ) levels. 41In this study, we investigated the impact of chronic hypoxia on the miR-146a/CXCR4 regulatory axis during monocytopoiesis and in monocytic leukemic cells. The levels of hypoxia studied were mild (5% O 2 ), such as that present in the sinusoidal cavity of bone marrow, and more severe (1% O 2 ), such as that in hypoxic niches in bone marrow.Altogether, our data demonstrated how the differential expression of HIF-1α and HIF-2α is mediated by O 2 level (mild or severe) and down-regulates CXCR4 expression through a post-transcriptional mechanism mediated by up-regulation of miR-146a in normal monocytic cells and in monocytic leukemia cell lines, expressing a moderate level of CXCR4. However, this mechanism is dysregulated in primary AML-M5 blast cells that fail to decrease CXCR4 expression significantly in response to hypoxia. This dysregulation helps to explain why leukemic blasts express high CXCR4 levels, even in hypoxic conditions, and how they are protected from anti-leukemic drugs through CXCR4 activation mediated by SDF-1α secreted in the hypoxic bone marrow microenvironment. MethodsAdditional information is provided in the Online Supplement. Cell culturesAfter obtaining informed consent, human cord blood was taken from healthy donors and samples of blood were taken from patients with AML. This study was approved by the local ethical committees of the Italian National Institute of Health and the University of Tor Vergata.Cord blood CD34 + hematopoietic progenitor cell purification, unilineage monocytic differentiation and morphological analyses were performed as previously described. 39 Human primary AML-M5 blasts were maintained in culture in vitro in Iscove medium supplemented with 10% fetal calf serum, granulocyte-macrophage colony-stimulating factor (10 ng/mL), stem cell factor (50 ng/mL), and interleukin-3 (10 ng/mL) (PeproTech Inc. Rocky Hill, NJ, USA). RNA and protein samples were prepared as described elsewhere. 39 Leukemic cell lines, U937 and HL-60, were grown in RPMI medium supplemented with 10% fetal calf serum (Gibco, Carlsbad, CA, USA). HypoxiaTo provide a mild or more severe hypoxic environment, acute ...

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Hypoxia-regulated target genes implicated in tumor metastasis

Cited by 173 publications

References 78 publications

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

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