Micromanaging Iron Homeostasis: Hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins

From the Integrative Bioscience and Biomedical Engineering, Graduate School of Science and Engineering, Waseda University, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2012; 287(41):34110-9. DOI: 10.1074/jbc.M112.356717
Source: PubMed


Iron is fundamental for sustaining life for living organisms, and the iron metabolism is finely regulated at different levels.
In cancer cells, deregulation of the iron metabolism induces oxidative stress and drives tumor progression and metastasis;
however, the molecular mechanisms of iron homeostasis are not fully understood. Here we found that iron deficiency as well
as hypoxia promoted microRNA-210 (miR-210) expression. A central mediator of miR-210 transcriptional activation is the hypoxia-inducible
factor (HIF)-1α, and the hypoxia-response element in the miR-210 promoter is confirmed experimentally. This is in agreement
with the data from in vivo studies that have demonstrated the presence of miR-210-expressing cells at the chronic hypoxic regions of xenografted tumors.
Furthermore we found two essential molecules for iron homeostasis, iron-sulfur cluster scaffold protein (ISCU) and transferrin
receptor 1 (TfR), are a direct target of miR-210. Transfection of miR-210 decreases the uptake of transferrin by inhibiting
the expression of TfR. In addition, inhibition of miR-210 by anti-miR-210 up-regulates ISCU expression. These findings suggest
that miR-210 works as an iron sensor and is involved in the maintenance of iron homeostasis by sustaining the TfR expression
level to stimulate cell proliferation and promote cell survival in the hypoxic region within tumors.

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    • "Another group found that miR-210 is induced not only during hypoxia but also during iron deficiency. This study further identified that the expression of miR-210 is associated with chronic hypoxia in the TM, suggesting a modulatory role of miR-210 during apoptosis and proliferation in cancer cells in the chronic hypoxic TM.113 Despite the dysregulated expression of miRs that is induced by hypoxia in the TM, progress has been made in our understanding of the molecular mechanism underlying the miR biogenesis machinery. "
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    ABSTRACT: miRNAs (miRs) are short RNA molecules that are involved in the posttranscriptional regulation of mRNA. The roles of miRs in tumor pathogenesis have only recently become a focus of research. It is becoming increasingly clear that miRs are important regulators of apoptosis, proliferation, invasion, and metastasis in cancer cells during cancer genesis and progression, furthering our understanding of cancer. In the present review, we summarize and evaluate the recent advances in our understanding of the characteristics of miRs as well as their regulated functions in cancer stem cells (CSCs), the epithelial-mesenchymal transition (EMT), and the tumor microenvironment (TM), describing their roles in tumor pathogenesis and their possible use as new therapeutic targets and biomarkers.
    OncoTargets and Therapy 11/2013; 6:1675-1684. DOI:10.2147/OTT.S52730 · 2.31 Impact Factor
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    • "miR-210 is a hypoxia-inducible miRNA that is activated by the master regulator of hypoxic stress, hypoxia-inducible factor (HIF)-1alpha in a variety of cell types (Chan et al., 2012). This miRNA has been implicated in erythropoiesis (Kosaka et al., 2008), iron homeostasis (Yoshioka et al., 2012), angiogenesis (Fasanaro et al., 2008), and cancer (Huang et al., 2009), which are also conditions associated with hypoxic stress. This miRNA has also been implicated in the regulation of DNA repair pathways (Crosby et al., 2009). "
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    ABSTRACT: Circulating RNAs in human body fluids are promising candidates for diagnostic purposes. However, the biological significance of circulating RNAs remains elusive. Recently, small non-coding RNAs, microRNAs (miRNAs), were isolated from multiple human body fluids, and these "circulating miRNAs" have been implicated as novel disease biomarkers. Concurrently, miRNAs were also identified in the extracellular space associated with extracellular vesicles (EVs), which are small membrane vesicles secreted from various types of cells. The function of these secreted miRNAs has been revealed in several papers. Circulating miRNAs have been experimentally found to be associated with EVs; however, other types of extracellular miRNAs were also described. This review discusses studies related to extracellular miRNAs, including circulating miRNAs and secreted miRNAs, to highlight the importance of studying not only secreted miRNAs, but also circulating miRNAs to determine the contribution of extracellular miRNAs especially in cancer development.
    Frontiers in Genetics 09/2013; 4:173. DOI:10.3389/fgene.2013.00173
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    • "miR-203 participates in a regulatory network that modulates epithelial to mesenchymal transition [44] as well as to promote suppression immune [45]. miR-210 is induced under hypoxia and works as a iron sensor to stimulate cell proliferation and promote cell survival in the hypoxic region within tumor [46-48]. Further, this miRNA modulates the mitochondrial functioning and metabolism [49,50], represses FGFRL1 and E2F3 expression, which inhibits cell apoptosis in hypoxia response [51,52], predicts poor survival in patients with breast cancer [53] and activates notch signalling pathway in angiogenesis [54]. "
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    ABSTRACT: Background T-cell intracellular antigen (TIA) proteins function as regulators of cell homeostasis. These proteins control gene expression globally at multiple levels in response to dynamic regulatory changes and environmental stresses. Herein we identified a micro(mi)RNA signature associated to transiently TIA-depleted HeLa cells and analyzed the potential role of miRNAs combining genome-wide analysis data on mRNA and miRNA profiles. Results Using high-throughput miRNA expression profiling, transient depletion of TIA-proteins in HeLa cells was observed to promote significant and reproducible changes affecting to a pool of up-regulated miRNAs involving miR-30b-3p, miR125a-3p, miR-193a-5p, miR-197-3p, miR-203a, miR-210, miR-371-5p, miR-373-5p, miR-483-5p, miR-492, miR-498, miR-503-5p, miR-572, miR-586, miR-612, miR-615-3p, miR-623, miR-625-5p, miR-629-5p, miR-638, miR-658, miR-663a, miR-671-5p, miR-769-3p and miR-744-5p. Some up-regulated and unchanged miRNAs were validated and previous results confirmed by reverse transcription and real time PCR. By target prediction of the miRNAs and combined analysis of the genome-wide expression profiles identified in TIA-depleted HeLa cells, we detected connections between up-regulated miRNAs and potential target genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database analysis suggest that target genes are related with biological processes associated to the regulation of DNA-dependent transcription, signal transduction and multicellular organismal development as well as with the enrichment of pathways involved in cancer, focal adhesion, regulation of actin cytoskeleton, endocytosis and MAPK and Wnt signaling pathways, respectively. When the collection of experimentally defined differentially expressed genes in TIA-depleted HeLa cells was intersected with potential target genes only 7 out of 68 (10%) up- and 71 out of 328 (22%) down-regulated genes were shared. GO and KEGG database analyses showed that the enrichment categories of biological processes and cellular pathways were related with innate immune response, signal transduction, response to interleukin-1, glomerular basement membrane development as well as neuroactive ligand-receptor interaction, endocytosis, lysosomes and apoptosis, respectively. Conclusion All this considered, these observations suggest that individual miRNAs could act as potential mediators of the epigenetic switch linking transcriptomic dynamics and cell phenotypes mediated by TIA proteins.
    BMC Molecular Biology 02/2013; 14(1):4. DOI:10.1186/1471-2199-14-4 · 2.19 Impact Factor
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