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: 8.39). 05/2008; 15(4):667-71. DOI: 10.1038/sj.cdd.4402310
Source: PubMed

ABSTRACT 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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    • "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.
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    • "A wide array of miRNAs have been linked to the transcriptional response to hypoxia. There is an extensive and growing list of miRNAs regulated by hypoxia, either positively or negatively , in different experimental settings (Kulshreshtha et al., 2008; Loscalzo, 2010; Bussolati et al., 2012; Du et al., 2012; Fang et al., 2012; Guo et al., 2012; Voellenkle et al., 2012). Other miRNAs are hypoxia-independent , but are capable of negatively regulating HIF; these include miR-107, miR-17-92 and miR-519c, whose expression is induced by p53, c-myc and the hepatocyte growth factor (HGF), respectively (Taguchi et al., 2008; Cha et al., 2010; Yamakuchi et al., 2010). "
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    ABSTRACT: Living organisms are constantly exposed to environmental and genetic perturbations. Biological robustness enables these organisms to maintain their functional stability in the presence of external or internal changes. It has been proposed that microRNAs (miRNAs), small non-coding regulatory RNAs, contribute to robustness of gene regulatory networks. The hypoxic response is a major and well-characterized example of a cellular and systemic response to environmental stress that needs to be robust. miRNAs regulate the response to hypoxia, both at the level of the main transcription factor that mediates this response, the hypoxia-inducible factor (HIF), and at the level of one of the most important systemic outcomes of the response: angiogenesis. In this review, we will take the hypoxic response as a paradigm of miRNAs participating in circuits that provide robustness to biological responses. Developmental Dynamics, 2012. © 2012 Wiley Periodicals, Inc.
    Developmental Dynamics 12/2012; 241(12). DOI:10.1002/dvdy.23865 · 2.67 Impact Factor
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    • "In addition to post-transcriptional modification of HIF-1a/b by miRNAs, HIF-1 itself has been shown to regulate the expression of miRNAs (Galanis et al., 2008; Kulshreshtha et al., 2008) in dependence of oxygen availability (Kulshreshtha et al., 2007; Huang et al., 2009). It is likely that HIF-1 is a direct regulator of miRNA response to hypoxia in different cancer cell lines, because of the presence of putative HIF-1 binding sites, suggesting participation in tumorigenesis. "
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    ABSTRACT: The hypoxia-inducible factor-1 (HIF-1) is an oxygen-regulated transcriptional activator playing a pivotal role in mammalian physiology and disease pathogenesis, e.g., HIF-1 is indispensable in a broad range of developmental stages in different tumors. Its post-translational regulation via PHDs under the influence of hypoxia is widely investigated and accepted. Different non-hypoxic stimuli such as lipopolysaccharides (LPS), thrombin, and angiotensin II (Ang II), have been proven to enhance HIF-1 levels through activation of regulative mechanisms distinct from protein stabilization. Some of these stimuli specifically regulate HIF-1α at the transcriptional, post-transcriptional, or translational level, whereas others additionally influence post-translational modifications. Thus, it is difficult for the investigators to discern the impact of the different mechanisms leading to functional HIF-1 protein. Nevertheless, profound knowledge of additional regulatory networks appears to depict new therapeutic opportunities and thus is an interesting and important field for further investigations.
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