Or modest, changes were observed in mature microRNA production. Conclusion: These observations provide further and

Or modest, changes were observed in mature microRNA production. Conclusion: These observations provide further and important interfaces between oxygen availability and gene expression and a potential mechanistic explanation for the reduced levels of microRNAs observed in some cancers. They provide further support for the existence of feedback mechanisms in the regulation of the microRNA biogenesis pathway and the relative stability of microRNAs. Keywords: Hypoxia, MicroRNA, Breast cancer, Dicer, Drosha, OxygenBackground Hypoxia is a key feature of many cancers and the presence of hypoxia is associated with more aggressive and metastatic tumours [1-3]. The exposure of cells to hypoxia leads to the co-ordinated regulation of many genes. The protein products of these genes have a wide variety of critical roles in processes such as metabolism, angiogenesis, growth and apoptosis. Studies of the mechanisms underlying the regulation of such genes have implicated a central role for the transcription factor hypoxia inducible factor (HIF). Many cancers are characterised by enhanced HIF levels and increased expression of hypoxically regulated genes which correlate both with tumour aggression and patient outcome [4]. The extent to which hypoxia contributes to enhanced tumour aggression via metabolic* Correspondence: [email protected] 1 Renal Department, Flinders Medical Centre, Flinders University School of Medicine, Bedford Park, Adelaide, South Australia 5042, Australia Full list of author information is available at the end of the articlealterations, changes in gene expression and/or epigenetic modifications remains incompletely understood. In addition to the transcriptional regulation of mRNA, hypoxia can also Mitochondrial division inhibitor 1 solubility influence mRNA stability, translation, protein stability and microRNA generation. Hypoxia also leads to the co-ordinated repression of many genes but the mechanism for such effects is less well defined. MicroRNAs (miRNAs) are 17?2 nucleotide, noncoding, single stranded RNA molecules that are important regulators of gene expression. MicroRNAs are transcribed as primary transcripts (pri-miRNAs) by RNA Polymerase II [5] or III [6] enzymes. In the nucleus, primiRNAs are cleaved by the nuclear RNase III enzyme Drosha and cofactor protein DGCR8 (DiGeorge syndrome critical region gene 8) to generate a precursor miRNA (pre-miRNA) (about 70 nucleotides long) [7]. The pre-miRNAs are exported to the cytoplasm by the karyopherin, exportin-5 [8]. In the cytoplasm, pre-?2014 Bandara et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Bandara et al. BMC Cancer 2014, 14:533 http://www.biomedcentral.com/1471-2407/14/Page 2 ofmiRNAs are further cleaved by Dicer, a ribonuclease III enzyme [9,10], coupled with TARBP2 (Tar RNA binding protein 2) [11,12] to generate a 22 nucleotide double stranded miRNA duplex. One strand of the RNA duplex functions as the mature miRNA and often the passenger strand PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28404814 will be degraded by endonucleases [13]. In some instances the passenger strand (previously referred to as the st.