Abstract
MicroRNAs (miRNAs) are a class of 20–24 nt non-coding RNAs that regulate gene expression primarily through post-transcriptional repression or mRNA degradation in a sequence-specific manner. The roles of miRNAs are just beginning to be understood, but the study of miRNA function has been limited by poor understanding of the general principles of gene regulation by miRNAs. Here we used CNE cells from a human nasopharyngeal carcinoma cell line as a cellular system to investigate miRNA-directed regulation of VEGF and other angiogenic factors under hypoxia, and to explore the principles of gene regulation by miRNAs. Through computational analysis, 96 miRNAs were predicted as putative regulators of VEGF. But when we analyzed the miRNA expression profile of CNE and four other VEGF-expressing cell lines, we found that only some of these miRNAs could be involved in VEGF regulation, and that VEGF may be regulated by different miRNAs that were differentially chosen from 96 putative regulatory miRNAs of VEGF in different cells. Some of these miRNAs also co-regulate other angiogenic factors (differential regulation and co-regulation principle). We also found that VEGF was regulated by multiple miRNAs using different combinations, including both coordinate and competitive interactions. The coordinate principle states that miRNAs with independent binding sites in a gene can produce coordinate action to increase the repressive effect of miRNAs on this gene. By contrast, the competitive principle states when multiple miRNAs compete with each other for a common binding site, or when a functional miRNA competes with a false positive miRNA for the same binding site, the repressive effects of miRNAs may be decreased. Through the competitive principle, false positive miRNAs, which cannot directly repress gene expression, can sometimes play a role in miRNA-mediated gene regulation. The competitive principle, differential regulation, multi-miRNA binding sites, and false positive miRNAs might be useful strategies in the avoidance of unwanted cross-action among genes targeted by miRNAs with multiple targets.
Highlights
MicroRNAs were discovered over a decade ago but only in recent years have they been recognized as one of the major regulatory gene families in cells
Its expression is regulated by many factors [22,23] but it is not clear whether miRNA is involved in vascular endothelial growth factor (VEGF) regulation under hypoxia
A map of miRNA binding to VEGF 39 untranslational region (39-UTR) was generated and 2 binding site-condense regions (MBSCR) were observed, including nt160– 195 and nt820–860 (Fig. 1A)
Summary
MicroRNAs (miRNAs) were discovered over a decade ago but only in recent years have they been recognized as one of the major regulatory gene families in cells. As a new family of small noncoding RNA molecules with approximately 22 nucleotides, miRNAs regulate gene expression through translational repression or mRNA degradation in a sequence-specific manner [1,2,3,4]. They are known to be involved in gene functioning during development, cell proliferation, apoptosis, differentiation, and carcinogenesis [5,6,7,8,9,10,11]. Discovery of the principles of gene regulation by miRNAs would be helpful in the understanding of their highly complex interactions, and in turn, their biological significance
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