A microRNA component of the hypoxic response. Cell Death Differ

Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA 02111, USA.
Cell Death and Differentiation (Impact Factor: 8.18). 05/2008; 15(4):667-71. DOI: 10.1038/sj.cdd.4402310
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microRNAs participate in a wide variety of physiological and pathological cellular processes. Recent studies have established a link between a specific group of microRNAs and hypoxia, a key feature of the neoplastic microenvironment. A significant proportion of the hypoxia-regulated microRNAs (HRMs) are also overexpressed in human cancers, suggesting a role in tumorigenesis. Preliminary evidence suggests that they could affect important processes such as apoptosis, proliferation and angiogenesis. Several HRMs exhibit induction in response to HIF activation, thus extending its repertoire of targets beyond translated genes. In the present review, we discuss the emerging roles of HRMs in oxygen deprivation in cancer context.

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Available from: Mircea Ivan, Mar 05, 2014
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    • "Although >2,000 miRNAs have been discovered in mammals, the functions of most miRNAs are not understood. Recent studies revealed that a significant proportion of hypoxia-regulated miRNAs were overexpressed in human cancers and could affect important processes, such as apoptosis, proliferation, and angiogenesis29. For instance, miR-210, miR-199a, and miR-34a-5p were reported to regulate hypoxia and angiogenesis303132. MiR-182 promoted proliferation and invasion of human prostate cancer cells by directly suppressing NDRG133. "
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    ABSTRACT: Hypoxia and reoxygenation are common characteristics of solid tumors, which lead to oxidative stress and activation of stress-response genes. Previously, we observed that N-myc downstream-regulated gene 1 (NDRG1) was strongly down-regulated after shifting to reoxygenation, but the regulatory mechanism of NDRG1 remained elusive. Here we focused on the regulation of NDRG1 by microRNAs (miRNAs). Breast cancer MCF-7 cells were cultured under hypoxia for 24 h followed by 24 h of reoxygenation. The miRNA profiles were examined by Nanostring nCounter assays. Forty-three miRNAs had significant changes upon reoxygenation. In silico analysis identified four oxygen-sensitive miRNAs whose seed regions perfectly matched the 3'-UTR of NDRG1. In particular, miR-769-3p was able to inhibit the expression of NDRG1, which caused a significant reduction of NDRG1 protein upon reoxygenation. Furthermore, overexpression of miR-769-3p significantly inhibited cell proliferation and enhanced apoptosis. Our results revealed that miR-769-3p can functionally regulate NDRG1 during changes in oxygen concentration.
    Scientific Reports 08/2014; 4:5908. DOI:10.1038/srep05908 · 5.58 Impact Factor
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    • "MiRNA expression can be influenced by changes in the tumor microenvironment [21,22] including conditions like tumor hypoxia [23-26]. The miRNA response to hypoxia, which is often cell-type specific, suggests miRNAs are intimately involved in the cellular reaction to hypoxia [23,24,26] and some are in turn involved in feedback mechanisms that regulate HIF [27-32]. Interestingly, many hypoxia responsive miRNAs (HRMs) are also upregulated in cancer suggesting they also function in tumorigenesis and/or tumor progression [26]. "
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    ABSTRACT: Background Hypoxia is often encountered in solid tumors and known to contribute to aggressive tumor behavior, radiation- and chemotherapy resistance resulting in a poor prognosis for the cancer patient. MicroRNAs (miRNAs) play a role in the regulation of the tumor cell response to hypoxia, however, not much is known about the involvement of miRNAs in hypoxic signalling pathways in soft tissue sarcomas (STS). Method A panel of twelve STS cell lines was exposed to atmospheric oxygen concentrations (normoxia) or 1% oxygen (hypoxia) for up to 48 h. Hypoxic conditions were verified and miRNA expression profiles were assessed by LNA™ oligonucleotide microarrays and RT-PCR after 24 h. The expression of target genes regulated by hypoxia responsive miRNAs is examined by end-point PCR and validated by luciferase reporter constructs. Results Exposure of STS cell lines to hypoxic conditions gave rise to upregulation of Hypoxia Inducible Factor (HIF) 1α protein levels and increased mRNA expression of HIF1 target genes CA9 and VEGFA. Deregulation of miRNA expression after 24 h of hypoxia was observed. The most differentially expressed miRNAs (p < 0.001) in response to hypoxia were miR-185-3p, miR-485-5p, miR-216a-5p (upregulated) and miR-625-5p (downregulated). The well-known hypoxia responsive miR-210-3p could not be reliably detected by the microarray platform most likely for technical reasons, however, its upregulation upon hypoxic stress was apparent by qPCR. Target prediction algorithms identified 11 potential binding sites for miR-485-5p and a single putative miR-210-3p binding site in the 3’UTR of HIF3α, the least studied member of the HIF family. We showed that HIF3α transcripts, expressing a 3’UTR containing the miR-485-5p and miR-210-3p target sites, are expressed in all sarcoma cell lines and upregulated upon hypoxia. Additionally, luciferase reporter constructs containing the 3’UTR of HIF3α were used to demonstrate regulation of HIF3α by miR-210-3p and miR-485-5p. Conclusion Here we provide evidence for the miRNA mediated regulation of HIF3α by hypoxia responsive miRNAs in STS, which may help to tightly regulate and fine-tune the hypoxic response. This provides a better insight into the mechanisms underlying the hypoxic response in STS and may ultimately yield information on novel prognostic and predictive markers or targets for treatment.
    BMC Cancer 06/2014; 14(1):429. DOI:10.1186/1471-2407-14-429 · 3.36 Impact Factor
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    • "Recent studies indicate that HIF-1 directly activates a number of hypoxia-responsive microRNAs (HRMs) such as miR-210 and miR-373 which are involved in the regulation of a variety of celland tissue-specific responses to hypoxia (Kulshreshtha et al., 2008; Crosby et al., 2009). Because HRMs are implicated in diverse physiological processes, we speculated that the effects of hypoxia on adrenal steroidogenesis may be mediated by certain HIF1- regulated miRNAs. "
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    ABSTRACT: Although numerous studies have shown that hypoxia affects cortisol and aldosterone production in vivo, the underlying molecular mechanisms regulating the steroidogenic genes of these steroid hormones are still poorly known. MicroRNAs are post-transcriptional regulators that control diverse biological processes and this study describes the identification and validation of the hypoxia-inducible microRNA, miR-10b, as a negative regulator of the CYP11B1 and CYP11B2 steroidogenic genes in H295R human adrenocortical cells. Using the human TaqMan Low Density miRNA Arrays, we determined the miRNA expression patterns in H295R cells under normoxic and hypoxic conditions, and in cells overexpressing the human HIF-1α. Computer analysis using three in silico algorithms predicted that the hypoxia-inducible miR-10b molecule targets CYP11B1 and CYP11B2 mRNAs. Gene transfection studies of luciferase constructs containing the 3'-untranslated region of CYP11B1 or CYP11B2, combined with miRNA overexpression and knockdown experiments provide compelling evidence that CYP11B1 and CYP11B2 mRNAs are likely targets of miR-10b.
    Marine Pollution Bulletin 04/2014; 85(2). DOI:10.1016/j.marpolbul.2014.04.002 · 2.99 Impact Factor
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