DIANA-microT web server: elucidating microRNA functions through target prediction

MicroRNAs (miRNAs) modulate complex physiological and pathological processes by repressing expression of multiple components of cellular regulatory networks. Here we demonstrate that miRNAs encoded by the miR-23∼27∼24 gene clusters are enriched in endothelial cells and highly vascularized tissues. Inhibition of miR-23 and miR-27 function by locked nucleic acid-modified anti-miRNAs represses angiogenesis in vitro and postnatal retinal vascular development in vivo. Moreover, miR-23 and miR-27 are required for pathological angiogenesis in a laser-induced choroidal neovascularization mouse model. MiR-23 and miR-27 enhance angiogenesis by promoting angiogenic signaling through targeting Sprouty2 and Sema6A proteins, which exert antiangiogenic activity. Manipulating miR-23/ 27 levels may have important therapeutic implications in neovascular age-related macular degeneration and other vascular disorders.blindness | MAP kinase signaling | semaphorins | Akt | proangiogenic T he growth of blood vessels through angiogenesis is a delicately controlled process that involves endothelial cell (EC) activation, proliferation, migration, and maturation (1). Physiological angiogenesis is required for normal vascular development as well as vascular homeostasis during adulthood. Pathological angiogenesis, commonly induced by tissue ischemia or inflammation, underlies numerous vascular disorders, such as age-related macular degeneration (AMD), a leading cause of blindness in the elderly (2). Choroidal neovascularization (CNV), which involves abnormal growth of blood vessels in the back of the eye, is a hallmark of neovascular AMD (3). Although the pathogenic mechanisms underlying AMD are still largely unknown, vascular endothelial growth factor (VEGF) has been shown to play a causal role in the development of CNV (4). Anti-VEGF agents have demonstrated efficacy in treating CNV in neovascular AMD (5, 6) but have limited efficacy and potential side effects (7,8).Recent studies have revealed important roles for microRNAs (miRNAs) in cardiovascular diseases and other disorders (9). miRNAs are small noncoding RNAs that negatively regulate gene expression by inducing mRNA degradation or inhibiting translation through binding to the 3′ untranslated region (3′UTR) of target mRNAs (10). Often, miRNAs modulate broad collections of mRNAs encoding multiple components of complex biological pathways. Several miRNAs have been implicated in angiogenesis (11,12). A group of miRNAs has also been shown to be substantially decreased in a laser-induced CNV model (13).The miR-23∼27∼24 clusters are highly expressed in ECs (14-17). Two miR-23∼27∼24 clusters exist in the vertebrate genome: an intergenic miR-23a∼27a∼24-2 cluster and an intronic miR23b∼27b∼24-1 cluster. Members of these clusters are involved in cell cycle control, proliferation, and differentiation of various cell types (18). Here, we show that inhibition of miR-23/27 impairs angiogenesis in vitro and postnatal retinal vascular development in vivo. Moreover, silencing of miR-23/27 suppresses l...

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“…S1C). miR-23a and miR-23b share most, if not all, predicted target genes by TargetScan and DIANA Lab, as do miR-27a and miR-27b (19,20).…”

Section: Resultsmentioning

confidence: 95%

“…S1C). miR-23a and miR-23b share most, if not all, predicted target genes by TargetScan and DIANA Lab, as do miR-27a and miR-27b (19,20).Northern-blot analyses revealed that miR-23a/b, miR-27a/b, and miR-24 are expressed at the highest levels in the lung and heart, which are highly vascularized tissues (Fig. 1B).…”

mentioning

confidence: 93%

Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23∼27∼24 clusters

Zhou¹,

Gallagher²,

Ufret-Vincenty³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

316

287

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“…42 In addition, mRNAs predicted by both the miRWalk and DIANA-microT algorithms to be targets of the 28 altered miRNAs were downloaded from the miRWalk database. 42,45 Pathway analysis was performed on the validated mRNA targets using IPA ® (Ingenuity ® Systems), and the validated and predicted data sets were mined for mRNAs known to be involved in epigenetic modification. 43,44 Real-time PCR.…”

Section: Methodsmentioning

confidence: 99%

“…components of the epigenetic machinery. We mined our validated data set, plus a predicted data set (targets predicted by miRWalk and DIANA-microT), 42,45 for mRNAs known to be involved in DNA methylation or histone modification. In total, 25 components of the epigenetic machinery were shown to be targets of the altered miRNAs [78 interactions: 5 validated and 73 predicted, respectively ( Table 2)].…”

mentioning

confidence: 99%

Smoking induces differential miRNA expression in human spermatozoa: A potential transgenerational epigenetic concern?

et al. 2012

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“…To investigate the mechanism through which miR-135a induced apoptosis of malignant glioma, we searched putative target genes by using TargetScan (Lewis et al, 2005) and DIANA-microT (Maragkakis et al, 2009) algorithms, and suggested that STAT6 and SMAD5 may associate with apoptosis (Sun et al, 2005;Zhang et al, 2008). We firstly transfected miR-135a and examined the protein levels of STAT6 and SMAD5 by western blotting.…”

Section: Mir-135a Targets Genes Associated With Mitochondrial Apoptotmentioning

confidence: 99%

MiR-135a functions as a selective killer of malignant glioma

Lin

et al. 2011

Oncogene

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Glioma is the most common and fatal primary brain tumor. Thus far, therapeutic strategies to efficiently and specifically antagonize glioma are limited and poorly developed. Here we report that glia-enriched miR-135a, a microRNA that is dramatically downregulated in malignant glioma and correlated with the pathological grading, is capable of inducing mitochondria-dependent apoptosis of malignant glioma by regulating various genes including STAT6, SMAD5 and BMPR2, as well as affecting the signaling pathway downstream. Moreover, this lethal effect is selectively towards malignant glioma cells, but not neurons and glial cells, through a novel mechanism. Our findings suggest an important role of miR-135a in glioma etiology and provide a potential candidate for malignant glioma therapy.

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DIANA-microT web server: elucidating microRNA functions through target prediction

Cited by 506 publications

References 14 publications

Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23∼27∼24 clusters

Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23∼27∼24 clusters

Smoking induces differential miRNA expression in human spermatozoa: A potential transgenerational epigenetic concern?

MiR-135a functions as a selective killer of malignant glioma

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