MiRNA-Directed Regulation of VEGF and Other Angiogenic Factors under Hypoxia

By Zhong Hua, Q. Lv, Wenbin Ye, Chung-Kwun Amy Wong, G. Cai, D. Gu, Yan-xia Ji, Chen Zhao, Jifeng Wang, Burton B. Yang and 1 more. PLoS ONE, 2006

691 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b885735c18589f86f13ce6409785ceccf4b2c16a

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Citations in the corpus

Tumor angiogenesis: molecular pathways and therapeutic targets (2011, background): “For example, a handful of miRNAs function both coordinately and competitively to regulate VEGF expressio”
Role of microRNAs in vascular diseases, inflammation, and angiogenesis. (2008, background): “55 Similarly, a broad effect has been demonstrated for miR-15 and miR-16, which are both downregulated by hypoxia in a carcinoma cell line and regulate the expression of VEGF.”
MicroRNAs in cancer: small molecules with a huge impact. (2009, background): “miR-221 and miR-222 repress proliferative and angiogenic properties of c-Kit in endothelial cells,(75) whereas hypoxic reduction of miR-16, miR-15b, miR-20a, and miR-20b, directly targeting vascular endothelial growth factor, supports the angiogenic process.(76) On the other hand, vascular endotheli”