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Vol. 19, Issue 8, 3272-3282, August 2008

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MicroRNA-21 Targets Sprouty2 and Promotes Cellular Outgrowths

Danish Sayed^*, Shweta Rane^*, Jacqueline Lypowy^*,, Minzhen He^*, Ieng-Yi Chen^*, Himanshu Vashistha, Lin Yan^*, Ashwani Malhotra, Dorothy Vatner^*, and Maha Abdellatif^*

*Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, and Department of Medicine, and Division of Nephrology, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103

Submitted February 15, 2008; Revised May 19, 2008; Accepted May 21, 2008
Monitoring Editor: Jonathan Chernoff

The posttranscriptional regulator, microRNA-21 (miR-21), is up-regulated in many forms of cancer, as well as during cardiac hypertrophic growth. To understand its role, we overexpressed it in cardiocytes where it revealed a unique type of cell-to-cell "linker" in the form of long slender outgrowths and branches. We subsequently confirmed that miR-21 directly targets and down-regulates the expression of Sprouty2 (SPRY2), an inhibitor of branching morphogenesis and neurite outgrowths. We found that β-adrenergic receptor (βAR) stimulation induces up-regulation of miR-21 and down-regulation of SPRY2 and is, likewise, associated with connecting cell branches. Knockdown of SPRY2 reproduced the branching morphology in cardiocytes, and vice versa, knockdown of miR-21 using a specific ‘miRNA eraser’ or overexpression of SPRY2 inhibited βAR-induced cellular outgrowths. These structures enclose sarcomeres and connect adjacent cardiocytes through functional gap junctions. To determine how this aspect of miR-21 function translates in cancer cells, we knocked it down in colon cancer SW480 cells. This resulted in disappearance of their microvillus-like protrusions accompanied by SPRY2-dependent inhibition of cell migration. Thus, we propose that an increase in miR-21 enhances the formation of various types of cellular protrusions through directly targeting and down-regulating SPRY2.

Present address: Department of Immunology, Merck & Co, Inc., 125 East Lincoln Avenue, Rahway, NJ 07065.

Address correspondence to: Maha Abdellatif (abdellma{at}umdnj.edu)

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