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MicroRNAs targeting carbohydrates open up new ways for cancer drug design

New research results from Uppsala University show that microRNAs, that regulate the formation of carbohydrates, affect cell behavior and potentially could be used as cancer drugs or drug targets. The study was recently published in The Journal of Biological Chemistry.



Johan KreugerAug. 12, 2013 — MicroRNAs are endogenous small RNAs that play important roles as regulators of gene expression to affect processes such as growth in animals. All cells in the body have molecules called proteoglycan co-receptors at the cell surface. These molecules help the cells to receive signals from neighboring cells. This is important, as cells in the body need to communicate in order to behave properly. The proteoglycans bind to potent growth factors via their heparan sulfate polysaccharide chains (a form of carbohydrate), and these can be regulated by microRNA. Deregulation of heparan sulfate production has been linked to diseases such as cancer and aberrant blood vessel formation.

ARTICLE CAPSULE


MicroRNA-24 suppression of N-deacetylase/N-sulfotransferase-1 (NDST1) reduces endothelial cell responsiveness to VEGFA 

Background: Heparan sulfate proteoglycan (HSPG) coreceptors modulate VEGFA signaling.

Results: MicroRNA-24 targets NDST1 to reduce HS sulfation and HS affinity for VEGFA, suppressing VEGFA signaling and endothelial cell migration.

Conclusion: MicroRNAs targeting HS biosynthesis can regulate VEGFA-induced chemotaxis, essential during angiogenesis.

Significance: HSPG-dependent signaling of pathophysiological importance can be targeted via microRNA interference with HS biosynthesis.

A group of researchers at Uppsala University, the Uppsala University Hospital and the Sahlgrenska Academy has made a discovery that for the first time show that microRNA, that affect the structure and functions of heparan sulfate in blood vessel cells, affect the ability of these cells to move. This in part promotes the formation of a new subfield within the proteoglycans research field.
 
Drugs targeting interactions between heparan sulfate and growth factors may be useful in treatment of diseases such as cancer and Alzheimer’s disease. For example, heparin, a member of the heparan sulfate family, has for a long time been used as a drug to prevent life-threatening blood clotting after surgery. Inhibition of the biosynthesis of heparin sulfate has been discussed as a possibility to treat cancer.
 
“We still do not fully understand how heparan sulfate biosynthesis is regulated, but it is possible that microRNAs suppressing heparan sulfate biosynthesis can be used as drugs in the future. For example, to dampen tumor-associated blood vessel growth or to make cancer cells less aggressive. But much research remains to be done to see if this can be possible. We are at the beginning of an exciting journey,” says Johan Kreuger, associate professor, Science for Life Laboratory, Uppsala University.
 
The study received funding from, among others, the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the Swedish Foundation for Strategic Research, and the Foundation for Proteoglycan Research at Uppsala University.

Press release courtesy of Uppsala University. You can find the original press release here.