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

被引:532
作者
Hua, Zhong [2 ]
Lv, Qing [2 ]
Ye, Wenbin [2 ]
Wong, Chung-Kwun Amy [1 ]
Cai, Guoping [2 ]
Gu, Dayong [2 ]
Ji, Yanhong [2 ]
Zhao, Chen [3 ]
Wang, Jifeng [4 ]
Yang, Burton B. [1 ]
Zhang, Yaou [2 ]
机构
[1] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Lab Med & Pathobiol, Toronto, ON, Canada
[2] Tsinghua Univ, Grad Sch Shenzhen, Div Life Sci, Shenzhen 518057, Peoples R China
[3] Xi An Jiao Tong Univ, Sch Life Sci & Technol, Xian 710049, Peoples R China
[4] Beijing Univ Chinese Med, Cell & Biochem Lab, Beijing, Peoples R China
来源
PLOS ONE | 2006年 / 1卷 / 02期
基金
中国国家自然科学基金; 加拿大健康研究院;
关键词
D O I
10.1371/journal.pone.0000116
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:13
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