Delivery of Therapeutics Targeting the mRNA Binding Protein HuR Using 3DNA Nanocarriers Suppresses Ovarian Tumor Growth

Yu Hung Huang, Weidan Peng, Narumi Furuuchi, Jacquelyn Gerhart, Kelly Rhodes, Neelanjan Mukherjee, Masaya Jimbo, Gregory E. Gonye, Jonathan R. Brody, Robert C. Getts, Janet A. Sawicki

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways 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 tumortargeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined 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.

Original languageEnglish (US)
Pages (from-to)1549-1559
Number of pages11
JournalCancer Research
Volume76
Issue number6
DOIs
StatePublished - Mar 15 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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