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Delivery of therapeutics targeting the mRNA-binding protein HuR using 3DNA nanocarriers suppresses ovarian tumor growth

Item Type:Article
Title:Delivery of therapeutics targeting the mRNA-binding protein HuR using 3DNA nanocarriers suppresses ovarian tumor growth
Creators Name:Huang, Y.H. and Peng, W. and Furuuchi, N. and Gerhart, J. and Rhodes, K. and Mukherjee, N. and Jimbo, M. and Gonye, G.E. and Brody, J.R. and Getts, R.C. and Sawicki, J.A.
Abstract:Growing evidence shows that cancer cells use mRNA-binding proteins and microRNAs to post-transcriptionally regulate signaling pathways in order to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumor-targeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA(R)). We combined small interfering RNAs (siRNAs) against HuR with FA-3DNA, and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumor bearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo targeted delivery of a cancer therapeutic, and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer.
Keywords:siRNA, Ovarian Cancer, HuR, Nanocarrier, Targeted, Animals, Mice
Source:Cancer Research
Publisher:American Association for Cancer Research
Page Range:1549-1559
Date:15 March 2016
Official Publication:https://doi.org/10.1158/0008-5472.CAN-15-2073
PubMed:View item in PubMed

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