Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver

By Joacim Elmén, M. Lindow, Asli Silahtaroglu, M. Bak, M. Christensen, A. Lind-Thomsen, Maj Hedtjärn, J. Hansen, H. Hansen, E. Straarup and 3 more. Nucleic Acids Research, 2007

703 citations recorded by the source corpus.

MicroRNA-122 (miR-122) is an abundant liver-specific miRNA, implicated in fatty acid and cholesterol metabolism as well as hepatitis C viral replication. Here, we report that a systemically administered 16-nt, unconjugated LNA (locked nucleic acid)-antimiR oligonucleotide complementary to the 5′ end of miR-122 leads to specific, dose-dependent silencing of miR-122 and shows no hepatotoxicity in mice. Antagonism of miR-122 is due to formation of stable heteroduplexes between the LNA-antimiR and miR-122 as detected by northern analysis. Fluorescence in situ hybridization demonstrated uptake of the LNA-antimiR in mouse liver cells, which was accompanied by markedly reduced hybridization signals for mature miR-122 in treated mice. Functional antagonism of miR-122 was inferred from a low cholesterol phenotype and de-repression within 24 h of 199 liver mRNAs showing significant enrichment for miR-122 seed matches in their 3′ UTRs. Expression profiling extended to 3 weeks after the last LNA-antimiR dose revealed that most of the changes in liver gene expression were normalized to saline control levels coinciding with normalized miR-122 and plasma cholesterol levels. Combined, these data suggest that miRNA antagonists comprised of LNA are valuable tools for identifying miRNA targets in vivo and for studying the biological role of miRNAs and miRNA-associated gene-regulatory networks in a physiological context.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/60621e0316131d463f9e522bb13ba7128a1ece3b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

Citations in the corpus

Silencing of microRNA families by seed-targeting tiny LNAs (2011, background): “Additionally, phosphorothioate backbone modifications provide high biostability and facilitate delivery of antimiRs to the live”
Therapeutic miRNA and siRNA: Moving from Bench to Clinic as Next Generation Medicine (2017, methodology): “In other study, Elmén et al.(76,77) used single LNA-anti-miR i.”
miRecords: an integrated resource for microRNA–target interactions (2008, background): “morpholinos (43), locked nucleic acids (44), or 20-O-Me oligonucleotides (45) and knockout of the miRNA gene (46).”
MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. (2012, neutral): “Thus, our data suggest that the pathway disturbances associated with Mir122a deletion contribute to tumor initiation and progression. our study differs from those using either in vivo knockdown of Mir122a (5, 6, 8, 38) or Dicer1 (17, 18).”
In vivo delivery of miRNAs for cancer therapy: Challenges and strategies (2014, background): “For example, a LNA-miRNA antagonist was developed to inhibit the function of miR-122 – a miRNA regulating HCV replication – in vitro and In vivo [105].”
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME (2013, positive): “Two studies could show that miR-122 appears to suppress 100–200 genes in liver tissue as demonstrated in mice (Esau et al. 2006; Elmen et al. 2008a).”
Development of microRNA therapeutics is coming of age (2014, neutral): “Furthermore, inhibition of miR-122 has been shown to lower both LDL cholesterol and HDL cholesterol levels mice and non-human primates (Elme´n et al , 2008b), which implies that miR-122 is not a good therapeutic target for reducing increased levels of LDL cholesterol in hypercholesterolemia.”
MicroRNAs in Common Human Diseases (2012, background): “This miRNA drug demonstrated impressive repression efficacy on miR-122 in mice [105] and in African green monkeys [106], as well as anti-viral efficacy in chimpanzees chronically infected by HCV [74].”